Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.

See related patient information

The disabling effects of tinnitus resemble those of chronic pain.¹ Specifically, its consequences may include:

• Loss of sleep
• Interference with concentration
• Difficulties functioning at work, at home, and in social relationships
• Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.^2,3

Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.^4–7

Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.

The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.

WHAT CAUSES TINNITUS?

The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.

If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.⁸

Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.⁹

Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.¹⁰ For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.^11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.

Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.

RULING OUT HEALTH-THREATENING DISEASE

The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.

Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.

At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.¹³

WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?

A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.

Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)¹⁴ consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.

SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS

Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.

AUDIOLOGY: TESTING, SOUND THERAPY

A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.¹⁵

Real sounds mask the perceived ones

Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.

Hearing aids amplify ambient sounds, reducing the perception of tinnitus.^16,17 They also improve communication.

Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.

Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.

Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.

Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.^18,19

DENTISTRY: TREATING TINNITUS BY TREATING TMD

Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.^20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.²²

There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.

The dental examination for tinnitus patients

The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.

The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.

How tinnitus is treated by managing TMD

Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.^23–25

Tullberg and Ernberg²⁶ treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.

A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.

In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.

NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION

The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.

Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),²⁷ or other cranial nerve disorders such as Bell palsy (facial nerve injury)²⁸ or trigeminal neuralgia.

Medical and surgical interventions for tinnitus-associated neurologic conditions

In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.

At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)²⁹ may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising³⁰; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.^31,32

In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)^33,34 are being evaluated and show potential for managing tinnitus.

PHYSICAL THERAPY

A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.

Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.^{11,24–26,35}

PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY

Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.³⁶ Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.

When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.³⁷ Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.

One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:

• The THI-S (Table 3)¹⁴
• The Patient Health Questionnaire-9 (PHQ-9)³⁸
• The Generalized Anxiety Disorder-7 (GAD-7).³⁹

Suicidal ideas need to be addressed

The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.

The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.

Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.

Treatments for depression and anxiety in tinnitus patients

Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:

Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.

Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.⁴⁰

Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.

See related patient information

The disabling effects of tinnitus resemble those of chronic pain.¹ Specifically, its consequences may include:

• Loss of sleep
• Interference with concentration
• Difficulties functioning at work, at home, and in social relationships
• Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.^2,3

Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.^4–7

Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.

The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.

WHAT CAUSES TINNITUS?

The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.

If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.⁸

Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.⁹

Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.¹⁰ For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.^11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.

Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.

RULING OUT HEALTH-THREATENING DISEASE

The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.

Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.

At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.¹³

WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?

A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.

Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)¹⁴ consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.

SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS

Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.

AUDIOLOGY: TESTING, SOUND THERAPY

A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.¹⁵

Real sounds mask the perceived ones

Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.

Hearing aids amplify ambient sounds, reducing the perception of tinnitus.^16,17 They also improve communication.

Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.

Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.

Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.

Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.^18,19

DENTISTRY: TREATING TINNITUS BY TREATING TMD

Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.^20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.²²

There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.

The dental examination for tinnitus patients

The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.

The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.

How tinnitus is treated by managing TMD

Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.^23–25

Tullberg and Ernberg²⁶ treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.

A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.

In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.

NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION

The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.

Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),²⁷ or other cranial nerve disorders such as Bell palsy (facial nerve injury)²⁸ or trigeminal neuralgia.

Medical and surgical interventions for tinnitus-associated neurologic conditions

In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.

At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)²⁹ may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising³⁰; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.^31,32

In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)^33,34 are being evaluated and show potential for managing tinnitus.

PHYSICAL THERAPY

A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.

Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.^{11,24–26,35}

PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY

Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.³⁶ Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.

When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.³⁷ Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.

One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:

• The THI-S (Table 3)¹⁴
• The Patient Health Questionnaire-9 (PHQ-9)³⁸
• The Generalized Anxiety Disorder-7 (GAD-7).³⁹

Suicidal ideas need to be addressed

The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.

The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.

Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.

Treatments for depression and anxiety in tinnitus patients

Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:

Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.

Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.⁴⁰

Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.

See related patient information

The disabling effects of tinnitus resemble those of chronic pain.¹ Specifically, its consequences may include:

• Loss of sleep
• Interference with concentration
• Difficulties functioning at work, at home, and in social relationships
• Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.^2,3

Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.^4–7

Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.

The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.

WHAT CAUSES TINNITUS?

The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.

If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.⁸

Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.⁹

Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.¹⁰ For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.^11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.

Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.

RULING OUT HEALTH-THREATENING DISEASE

The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.

Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.

At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.¹³

WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?

A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.

Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)¹⁴ consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.

SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS

Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.

AUDIOLOGY: TESTING, SOUND THERAPY

A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.¹⁵

Real sounds mask the perceived ones

Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.

Hearing aids amplify ambient sounds, reducing the perception of tinnitus.^16,17 They also improve communication.

Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.

Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.

Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.

Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.^18,19

DENTISTRY: TREATING TINNITUS BY TREATING TMD

Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.^20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.²²

There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.

The dental examination for tinnitus patients

The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.

The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.

How tinnitus is treated by managing TMD

Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.^23–25

Tullberg and Ernberg²⁶ treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.

A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.

In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.

NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION

The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.

Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),²⁷ or other cranial nerve disorders such as Bell palsy (facial nerve injury)²⁸ or trigeminal neuralgia.

Medical and surgical interventions for tinnitus-associated neurologic conditions

In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.

At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)²⁹ may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising³⁰; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.^31,32

In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)^33,34 are being evaluated and show potential for managing tinnitus.

PHYSICAL THERAPY

A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.

Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.^{11,24–26,35}

PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY

Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.³⁶ Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.

When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.³⁷ Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.

One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:

• The THI-S (Table 3)¹⁴
• The Patient Health Questionnaire-9 (PHQ-9)³⁸
• The Generalized Anxiety Disorder-7 (GAD-7).³⁹

Suicidal ideas need to be addressed

The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.

The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.

Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.

Treatments for depression and anxiety in tinnitus patients

Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:

Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.

Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.⁴⁰

Use sound to:

• Take attention away from your tinnitus
• Improve your sleep
• Improve your concentration
• Improve your relaxation

Two ways of using sound for your tinnitus

• Create a background sound to make the tinnitus less noticeable (eg, fan noise, radio,TV, nature sounds, water sounds)
• Use attention-getting sound to distract you from your tinnitus (lectures, books on tape, talk shows, conversation)

Three steps to determine the best use of sound for your tinnitus

• Identify specific situations when your tinnitus is most bothersome
• Determine which type of sound would be most helpful in each situation
• Determine the best device for presenting the sound in each situation

Obtain and use devices that produce sounds you like

• Background sounds from CDs
• Tabletop devices (eg, sound machines, water fountains)
• Portable listening devices (eg, MP3 player with music)

Protect your ears

• Loud noise can make your tinnitus worse (and damage your hearing)
• Always use earplugs or earmuffs around loud noise

Optimize your lifestyle and minimize tinnitus by

• Getting adequate sleep
• Reducing stress
• Reducing coffee, alcohol, cigarettes, aspirin, salt
• Eating healthy
• Exercising
• Staying busy with meaningful activities
• Becoming aware of your posture
• Taking breaks from work at the computer every 30 minutes to promote proper posture

Become educated about your tinnitus

• Join the American Tinnitus Association (www.ata.org)
• Read The Mindfulness and Acceptance Workbook for Anxiety (JP Forsyth & GH Eifert)

CDs that produce various background sounds

(We offer the following as suggestions, but do not provide a product endorsement.)

• www.sleepmachines.com
• www.binaural.com/bines.html
• www.naturesounds.com
• www.purewhitenoise.com
• www.soundpillow.com
• www.t-gone.com/white-noise

Tabletop devices

• www.sharperimage.com
• www.brookstone.com
• www.marpac.com
• www.simplyfountains.com

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health

Use sound to:

• Take attention away from your tinnitus
• Improve your sleep
• Improve your concentration
• Improve your relaxation

Two ways of using sound for your tinnitus

• Create a background sound to make the tinnitus less noticeable (eg, fan noise, radio,TV, nature sounds, water sounds)
• Use attention-getting sound to distract you from your tinnitus (lectures, books on tape, talk shows, conversation)

Three steps to determine the best use of sound for your tinnitus

• Identify specific situations when your tinnitus is most bothersome
• Determine which type of sound would be most helpful in each situation
• Determine the best device for presenting the sound in each situation

Obtain and use devices that produce sounds you like

• Background sounds from CDs
• Tabletop devices (eg, sound machines, water fountains)
• Portable listening devices (eg, MP3 player with music)

Protect your ears

• Loud noise can make your tinnitus worse (and damage your hearing)
• Always use earplugs or earmuffs around loud noise

Optimize your lifestyle and minimize tinnitus by

• Getting adequate sleep
• Reducing stress
• Reducing coffee, alcohol, cigarettes, aspirin, salt
• Eating healthy
• Exercising
• Staying busy with meaningful activities
• Becoming aware of your posture
• Taking breaks from work at the computer every 30 minutes to promote proper posture

Become educated about your tinnitus

• Join the American Tinnitus Association (www.ata.org)
• Read The Mindfulness and Acceptance Workbook for Anxiety (JP Forsyth & GH Eifert)

CDs that produce various background sounds

(We offer the following as suggestions, but do not provide a product endorsement.)

• www.sleepmachines.com
• www.binaural.com/bines.html
• www.naturesounds.com
• www.purewhitenoise.com
• www.soundpillow.com
• www.t-gone.com/white-noise

Tabletop devices

• www.sharperimage.com
• www.brookstone.com
• www.marpac.com
• www.simplyfountains.com

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health

Use sound to:

• Take attention away from your tinnitus
• Improve your sleep
• Improve your concentration
• Improve your relaxation

Two ways of using sound for your tinnitus

• Create a background sound to make the tinnitus less noticeable (eg, fan noise, radio,TV, nature sounds, water sounds)
• Use attention-getting sound to distract you from your tinnitus (lectures, books on tape, talk shows, conversation)

Three steps to determine the best use of sound for your tinnitus

• Identify specific situations when your tinnitus is most bothersome
• Determine which type of sound would be most helpful in each situation
• Determine the best device for presenting the sound in each situation

Obtain and use devices that produce sounds you like

• Background sounds from CDs
• Tabletop devices (eg, sound machines, water fountains)
• Portable listening devices (eg, MP3 player with music)

Protect your ears

• Loud noise can make your tinnitus worse (and damage your hearing)
• Always use earplugs or earmuffs around loud noise

Optimize your lifestyle and minimize tinnitus by

• Getting adequate sleep
• Reducing stress
• Reducing coffee, alcohol, cigarettes, aspirin, salt
• Eating healthy
• Exercising
• Staying busy with meaningful activities
• Becoming aware of your posture
• Taking breaks from work at the computer every 30 minutes to promote proper posture

Become educated about your tinnitus

• Join the American Tinnitus Association (www.ata.org)
• Read The Mindfulness and Acceptance Workbook for Anxiety (JP Forsyth & GH Eifert)

CDs that produce various background sounds

(We offer the following as suggestions, but do not provide a product endorsement.)

• www.sleepmachines.com
• www.binaural.com/bines.html
• www.naturesounds.com
• www.purewhitenoise.com
• www.soundpillow.com
• www.t-gone.com/white-noise

Tabletop devices

• www.sharperimage.com
• www.brookstone.com
• www.marpac.com
• www.simplyfountains.com

This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.

This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.

For patient information on hundreds of health topics, see the Web site, www.clevelandclinic.org/health

A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.

His physical examination is normal. Routine laboratory testing shows the following:

• Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
• White blood cell count 6.7 × 10⁹/L (3.5–10.5)
• Platelet count 279 × 10⁹/L (150–450)
• Alkaline phosphatase 387 U/L (45–115)
• Total bilirubin 0.9 mg/dL (0.1–1.0)
• Aspartate aminotransferase (AST) 35 U/L (35–48)
• Alanine aminotransferase (ALT) 30 U/L (7–55).

WHAT IS THE DIAGNOSIS?

1. Based on this information, which of the following is the most likely diagnosis?

• Autoimmune hepatitis
• Primary sclerosing cholangitis
• Primary biliary cirrhosis
• Idiopathic adulthood ductopenia

Primary sclerosing cholangitis

The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:

• Characteristic cholangiographic abnormalities of the biliary tree
• Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
• Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.¹

At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.² In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.³ At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.⁴

Two large epidemiologic studies (one from Olmsted County, MN,⁵ the other from Swansea, Wales, UK⁶) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.

It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.⁵ In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.

Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,⁷ and it may cost less per diagnosis.⁸

Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.⁹

Autoimmune hepatitis

Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.¹⁰ Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels¹⁰—unlike the pattern in our patient.

Primary biliary cirrhosis

Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:

• Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
• Antimitochondrial antibody
• Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.¹¹

In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.

Idiopathic adulthood ductopenia

Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).¹² Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.^12,13

ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE

2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?

• Crohn disease of the small bowel is the most common form
• Liver disease often precedes the bowel disease
• Treating the underlying bowel disease improves the long-term prognosis for the liver condition
• Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone

From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.^14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.¹

Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.^15,16

No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.¹⁷

In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.¹⁸ Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.^19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.¹⁵

TREATMENT AND PROGNOSIS

After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.

3. Which is the only life-prolonging therapy for primary sclerosing cholangitis?

• Methotrexate (Trexall)
• Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
• UDCA at a high dosage (20–30 mg/kg/day)
• Liver transplantation

Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.

In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.^21–23

In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,^24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.^26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.²⁷ One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.²⁸ However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.

Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.²⁹ Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.³⁰ Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.³¹

4. In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?

• Colon cancer
• Cholangiocarcinoma
• Osteoporosis
• Fat-soluble vitamin deficiency
• All of the above

All are potential long-term complications.

Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.¹⁸ According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, ^19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.

Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.^1,20 In a retrospective study of 30 patients,³² the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.

At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.

Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.³³ A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.³⁴

Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.³⁵ Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis³⁶ and can be considered in patients with advanced osteoporosis.

Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.³⁷ Patients can undergo simple oral replacement therapy.

 

 

A stone is removed, fever develops

Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.

Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.

5. In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?

• ERCP
• MRCP
• Abdominal ultrasonography
• Abdominal CT

The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.³⁸ In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.

In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.³⁹ The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.³⁹

MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.^7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.

The patient undergoes ERCP with stenting

The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.

TAKE-HOME POINTS

• Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
• This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
• Cholangiocarcinoma and colon cancer are dreaded complications.
• Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.

A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.

His physical examination is normal. Routine laboratory testing shows the following:

• Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
• White blood cell count 6.7 × 10⁹/L (3.5–10.5)
• Platelet count 279 × 10⁹/L (150–450)
• Alkaline phosphatase 387 U/L (45–115)
• Total bilirubin 0.9 mg/dL (0.1–1.0)
• Aspartate aminotransferase (AST) 35 U/L (35–48)
• Alanine aminotransferase (ALT) 30 U/L (7–55).

WHAT IS THE DIAGNOSIS?

1. Based on this information, which of the following is the most likely diagnosis?

• Autoimmune hepatitis
• Primary sclerosing cholangitis
• Primary biliary cirrhosis
• Idiopathic adulthood ductopenia

Primary sclerosing cholangitis

The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:

• Characteristic cholangiographic abnormalities of the biliary tree
• Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
• Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.¹

At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.² In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.³ At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.⁴

Two large epidemiologic studies (one from Olmsted County, MN,⁵ the other from Swansea, Wales, UK⁶) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.

It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.⁵ In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.

Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,⁷ and it may cost less per diagnosis.⁸

Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.⁹

Autoimmune hepatitis

Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.¹⁰ Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels¹⁰—unlike the pattern in our patient.

Primary biliary cirrhosis

Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:

• Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
• Antimitochondrial antibody
• Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.¹¹

In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.

Idiopathic adulthood ductopenia

Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).¹² Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.^12,13

ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE

2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?

• Crohn disease of the small bowel is the most common form
• Liver disease often precedes the bowel disease
• Treating the underlying bowel disease improves the long-term prognosis for the liver condition
• Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone

From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.^14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.¹

Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.^15,16

No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.¹⁷

In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.¹⁸ Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.^19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.¹⁵

TREATMENT AND PROGNOSIS

After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.

3. Which is the only life-prolonging therapy for primary sclerosing cholangitis?

• Methotrexate (Trexall)
• Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
• UDCA at a high dosage (20–30 mg/kg/day)
• Liver transplantation

Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.

In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.^21–23

In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,^24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.^26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.²⁷ One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.²⁸ However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.

Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.²⁹ Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.³⁰ Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.³¹

4. In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?

• Colon cancer
• Cholangiocarcinoma
• Osteoporosis
• Fat-soluble vitamin deficiency
• All of the above

All are potential long-term complications.

Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.¹⁸ According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, ^19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.

Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.^1,20 In a retrospective study of 30 patients,³² the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.

At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.

Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.³³ A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.³⁴

Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.³⁵ Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis³⁶ and can be considered in patients with advanced osteoporosis.

Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.³⁷ Patients can undergo simple oral replacement therapy.

 

 

A stone is removed, fever develops

Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.

Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.

5. In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?

• ERCP
• MRCP
• Abdominal ultrasonography
• Abdominal CT

The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.³⁸ In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.

In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.³⁹ The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.³⁹

MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.^7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.

The patient undergoes ERCP with stenting

The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.

TAKE-HOME POINTS

• Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
• This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
• Cholangiocarcinoma and colon cancer are dreaded complications.
• Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.

A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.

His physical examination is normal. Routine laboratory testing shows the following:

• Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
• White blood cell count 6.7 × 10⁹/L (3.5–10.5)
• Platelet count 279 × 10⁹/L (150–450)
• Alkaline phosphatase 387 U/L (45–115)
• Total bilirubin 0.9 mg/dL (0.1–1.0)
• Aspartate aminotransferase (AST) 35 U/L (35–48)
• Alanine aminotransferase (ALT) 30 U/L (7–55).

WHAT IS THE DIAGNOSIS?

1. Based on this information, which of the following is the most likely diagnosis?

• Autoimmune hepatitis
• Primary sclerosing cholangitis
• Primary biliary cirrhosis
• Idiopathic adulthood ductopenia

Primary sclerosing cholangitis

The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:

• Characteristic cholangiographic abnormalities of the biliary tree
• Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
• Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.¹

At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.² In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.³ At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.⁴

Two large epidemiologic studies (one from Olmsted County, MN,⁵ the other from Swansea, Wales, UK⁶) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.

It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.⁵ In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.

Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,⁷ and it may cost less per diagnosis.⁸

Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.⁹

Autoimmune hepatitis

Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.¹⁰ Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels¹⁰—unlike the pattern in our patient.

Primary biliary cirrhosis

Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:

• Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
• Antimitochondrial antibody
• Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.¹¹

In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.

Idiopathic adulthood ductopenia

Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).¹² Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.^12,13

ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE

2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?

• Crohn disease of the small bowel is the most common form
• Liver disease often precedes the bowel disease
• Treating the underlying bowel disease improves the long-term prognosis for the liver condition
• Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone

From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.^14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.¹

Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.^15,16

No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.¹⁷

In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.¹⁸ Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.^19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.¹⁵

TREATMENT AND PROGNOSIS

After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.

3. Which is the only life-prolonging therapy for primary sclerosing cholangitis?

• Methotrexate (Trexall)
• Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
• UDCA at a high dosage (20–30 mg/kg/day)
• Liver transplantation

Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.

In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.^21–23

In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,^24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.^26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.²⁷ One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.²⁸ However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.

Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.²⁹ Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.³⁰ Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.³¹

4. In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?

• Colon cancer
• Cholangiocarcinoma
• Osteoporosis
• Fat-soluble vitamin deficiency
• All of the above

All are potential long-term complications.

Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.¹⁸ According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, ^19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.

Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.^1,20 In a retrospective study of 30 patients,³² the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.

At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.

Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.³³ A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.³⁴

Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.³⁵ Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis³⁶ and can be considered in patients with advanced osteoporosis.

Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.³⁷ Patients can undergo simple oral replacement therapy.

 

 

A stone is removed, fever develops

Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.

Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.

5. In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?

• ERCP
• MRCP
• Abdominal ultrasonography
• Abdominal CT

The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.³⁸ In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.

In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.³⁹ The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.³⁹

MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.^7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.

The patient undergoes ERCP with stenting

The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.

TAKE-HOME POINTS

• Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
• This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
• Cholangiocarcinoma and colon cancer are dreaded complications.
• Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.

A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.

Q: What is the diagnosis?

• Lupus vulgaris (tuberculosis of the skin)
• Wegener granulomatosis
• Midline lethal granuloma (natural killer T-cell lymphoma)
• Hansen disease (leprosy)
• Lupoid form of cutaneous leishmaniasis

A: Lupus vulgaris is the correct diagnosis.

Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.¹ Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.²

Several morphologic variants have been described.^1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.

CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS

A number of factors helped to confirm the diagnosis in this patient:

• A strongly positive Mantoux test (22-mm induration at 48 hours)
• Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
• Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium

• 

  A suggestive histopathologic picture (Figure 2)
• The features on presentation
• A significant clinical improvement within 2 months of starting antituberculosis therapy.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.

On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.

TREATMENT

Lupus vulgaris is treated with standard antituberculosis therapy.³ The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.³

Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.

A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.

Q: What is the diagnosis?

• Lupus vulgaris (tuberculosis of the skin)
• Wegener granulomatosis
• Midline lethal granuloma (natural killer T-cell lymphoma)
• Hansen disease (leprosy)
• Lupoid form of cutaneous leishmaniasis

A: Lupus vulgaris is the correct diagnosis.

Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.¹ Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.²

Several morphologic variants have been described.^1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.

CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS

A number of factors helped to confirm the diagnosis in this patient:

• A strongly positive Mantoux test (22-mm induration at 48 hours)
• Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
• Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium

• 

  A suggestive histopathologic picture (Figure 2)
• The features on presentation
• A significant clinical improvement within 2 months of starting antituberculosis therapy.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.

On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.

TREATMENT

Lupus vulgaris is treated with standard antituberculosis therapy.³ The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.³

Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.

A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.

Q: What is the diagnosis?

• Lupus vulgaris (tuberculosis of the skin)
• Wegener granulomatosis
• Midline lethal granuloma (natural killer T-cell lymphoma)
• Hansen disease (leprosy)
• Lupoid form of cutaneous leishmaniasis

A: Lupus vulgaris is the correct diagnosis.

Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.¹ Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.²

Several morphologic variants have been described.^1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.

CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS

A number of factors helped to confirm the diagnosis in this patient:

• A strongly positive Mantoux test (22-mm induration at 48 hours)
• Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
• Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium

• 

  A suggestive histopathologic picture (Figure 2)
• The features on presentation
• A significant clinical improvement within 2 months of starting antituberculosis therapy.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.

On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.

TREATMENT

Lupus vulgaris is treated with standard antituberculosis therapy.³ The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.³

Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.

An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.

His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.

Q: What is the most likely diagnosis?

• Acute myocardial infarction
• Coronary vasospasm
• Brugada syndrome
• Acute pericarditis
• Acute meningitis

A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.¹ These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.

WHAT IS BRUGADA SYNDROME?

Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.² It accounts for 4% of all sudden deaths.³

Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V₁ to V₃). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.

Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:

• Documented ventricular fibrillation
• Polymorphic ventricular tachycardia
• A family history of sudden cardiac death at 45 years of age or younger
• Type 1 pattern on ECG in family members
• Ventricular tachycardia that can be induced with programmed electrical stimulation
• Syncope
• Nocturnal agonal respiration.³

This patient had type 1 changes on ECG but none of the above findings.

Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.³ These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.³

At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.⁴ Therefore, fever can unmask Brugada syndrome, as it did in our patient.

For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.⁵ Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.^3,5

CASE CONTINUED

The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.

Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.

On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.

As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.

An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.

His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.

Q: What is the most likely diagnosis?

• Acute myocardial infarction
• Coronary vasospasm
• Brugada syndrome
• Acute pericarditis
• Acute meningitis

A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.¹ These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.

WHAT IS BRUGADA SYNDROME?

Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.² It accounts for 4% of all sudden deaths.³

Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V₁ to V₃). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.

Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:

• Documented ventricular fibrillation
• Polymorphic ventricular tachycardia
• A family history of sudden cardiac death at 45 years of age or younger
• Type 1 pattern on ECG in family members
• Ventricular tachycardia that can be induced with programmed electrical stimulation
• Syncope
• Nocturnal agonal respiration.³

This patient had type 1 changes on ECG but none of the above findings.

Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.³ These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.³

At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.⁴ Therefore, fever can unmask Brugada syndrome, as it did in our patient.

For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.⁵ Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.^3,5

CASE CONTINUED

The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.

Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.

On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.

As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.

An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.

His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.

Q: What is the most likely diagnosis?

• Acute myocardial infarction
• Coronary vasospasm
• Brugada syndrome
• Acute pericarditis
• Acute meningitis

A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.¹ These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.

WHAT IS BRUGADA SYNDROME?

Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.² It accounts for 4% of all sudden deaths.³

Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V₁ to V₃). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.

Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:

• Documented ventricular fibrillation
• Polymorphic ventricular tachycardia
• A family history of sudden cardiac death at 45 years of age or younger
• Type 1 pattern on ECG in family members
• Ventricular tachycardia that can be induced with programmed electrical stimulation
• Syncope
• Nocturnal agonal respiration.³

This patient had type 1 changes on ECG but none of the above findings.

Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.³ These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.³

At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.⁴ Therefore, fever can unmask Brugada syndrome, as it did in our patient.

For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.⁵ Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.^3,5

CASE CONTINUED

The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.

Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.

On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.

As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.

This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?

We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?

Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.

A 57-year-old black woman presented to the emergency department with severe, dull abdominal pain associated with nonbilious vomiting and nausea. She had diabetes mellitus and hypertension, for which she had been taking metformin (Glucophage) 500 mg twice a day and lisinopril (available as Prinivil and Zestril) 20 mg daily for the last 4 years.

Multiple admissions in the past 4 years

The patient started taking lisinopril 10 mg daily in 2005, and she presented to her medical provider 2 weeks later with abdominal discomfort. Colonoscopy was performed, which revealed a benign polyp. She continued taking her medications, including lisinopril.

She continued to occasionally have abdominal pain of variable severity, but it was tolerable until 6 months later, when she presented to the emergency department with severe recurrent abdominal pain.

In view of the clinical picture, her physicians decided to treat her for small bowel obstruction, and an exploratory laparotomy was performed. The surgeons noted that she had moderate ascites, adhesions on the omentum, and a thickened high loop of the small bowel that was unequivocally viable and hyperemic, with thickening of the mesentery. Ascitic fluid was evacuated, adhesions were lysed, and the abdomen was closed. She was discharged with the same medications, including lisinopril; the dose was subsequently increased for better control of her hypertension.

The woman was admitted three more times within the same year for the same symptoms and underwent multiple workups for pancreatitis, gastritis, small-bowel obstruction, and other common gastrointestinal diseases.

Present admission

On review of systems, she denied any dry cough, weight loss or gain, food allergies, new medications, or hematochezia.

On physical examination, she had hypoactive bowel sounds and diffuse tenderness with guarding around the epigastric area.

Laboratory tests did not reveal any abnormalities; in particular, her C1 esterase concentration was normal. Stool studies were negative for infectious diseases.

Plain radiography of the abdomen showed a nonobstructive bowel-gas pattern.

She was diagnosed with gastrointestinal angioedema secondary to angiotensin-converting enzyme (ACE) inhibitor therapy. Her lisinopril was discontinued, and the symptoms resolved completely in 24 hours. On follow-up 8 weeks and 16 months later, her symptoms had not returned.

A RARE COMPLICATION OF ACE-INHIBITOR THERAPY

Angioedema occurs in 0.1% to 0.7% of patients taking ACE inhibitors, and it can affect about 1 of 2,500 patients during the first week of exposure.^1–3 It usually manifests as swelling of the face, tongue, and lips, and in rare cases, the gastrointestinal wall. Thus, visceral angioedema is a rare complication of ACE-inhibitor therapy.

Because angioedema is less obvious when it involves abdominal organs, it presents a diagnostic challenge. It is placed lower in the differential diagnosis, as other, more common, and occasionally more high-risk medical conditions are generally considered first. Most of the time, the diagnosis is missed. Some physicians may not be aware of this problem, since only a few case reports have been published. Nevertheless, this potential complication needs to be considered when any patient receiving ACE inhibitors for treatment of hypertension, myocardial infarction, heart failure, or diabetic nephropathy presents with diffuse abdominal pain, diarrhea, or edema of the upper airways.^4–8

If a high level of suspicion is applied along with good clinical judgment, then hospitalizations, unnecessary procedures, patient discomfort, and unnecessary health care costs can be prevented.

A MEDLINE SEARCH

To investigate the characteristics associated with this unusual presentation, including the time of symptom onset, the types of symptoms, and the diagnostic studies performed on the patients with visceral angioedema, we performed a MEDLINE search to identify case reports and case series published in English from 1980 to 2010 on the topic of abdominal or visceral angioedema. The search terms used were “visceral,” “intestinal angioedema,” “ACE-inhibitor side effects,” and the names of various ACE inhibitors.

Pertinent articles were identified, and clinical characteristics were collected, including demographics, onset of symptoms, the drug’s name, and others. In our summary below, data are presented as the mean and standard deviation for continuous variables and percentages for categorical variables.

SUMMARY OF REPORTED CASES

Our search revealed 27 reported cases of visceral angioedema associated with ACE inhibitors (a table summarizing our findings is available).^9–34 The drug most often involved was lisinopril (11 cases), followed by enalapril (Vasotec) (8 cases).

Twenty-three (82%) of the cases were in women. The mean age of the patients was 49.5 ± 12.2 years (range 29–77 years); the mean age was 46.7 ± 11.7 years in women and 57 ± 13 years in men. Unfortunately, the race and ethnicity of the patients was documented in only some cases.

In 15 (54%) of the cases, the patient presented to a physician or emergency department within 72 hours (41.1 ± 17.4) of starting therapy, and in 8 cases the patient presented between 2 weeks and 18 months.

In 10 cases (including the case we are reporting here), the patients were kept on ACE inhibitors from 2 to 9 years after the initial presentation, as the diagnosis was missed.^{9,12,14,18,20,31,32} In 2 cases, the dose of the ACE inhibitor had been increased after the patient presented with the abdominal pain.

All of the patients were hospitalized for further diagnostic workup.

As for the presenting symptoms, all the patients had abdominal pain, 24 (86%) had emesis, 14 (50%) had diarrhea, and 20 (71%) had ascites. Laboratory results were mostly nonspecific. Twelve (44%) of the patients had leukocytosis. The C1 esterase inhibitor concentration was measured in 18 patients, and the results were normal in all of them.

Twenty-four (86%) of the patients underwent abdominal and pelvic CT or ultrasonography as part of the initial diagnostic evaluation, and intestinal wall-thickening was found in 21 (87.5%) of them.

Either surgery or gastrointestinal biopsy was performed in 16 (57%) of the patients; the surgical procedures included 2 cholecystectomies and 1 bone marrow biopsy. Only 1 case was diagnosed on the basis of clinical suspicion and abdominal radiographs alone.

The combination of intestinal and stomach angioedema was found in only 2 cases.

Two patients were kept on an ACE inhibitor in spite of symptoms and intestinal wall edema that showed a migratory pattern on imaging after chronic exposure.

The thickening involved the jejunum in 14 patients (50%), the ileum in 8 (29%), the duodenum in 5 (18%), the stomach in 2, and the sigmoid colon in 1.

In 12 cases (43%), visceral angioedema and its symptoms resolved within 48 hours of stopping the ACE inhibitor.

A DIAGNOSIS TO KEEP IN MIND

As we have seen, the diagnosis of visceral angioedema needs to be kept in mind when a patient—especially a middle-aged woman—taking an ACE inhibitor presents with abdominal pain, vomiting, diarrhea, leukocytosis, ascites, and wall-thickening of the small bowel on imaging studies.^9,35,36

The diagnosis is hard to establish, and in the interim the patient may undergo invasive and unnecessary procedures, which can be avoided by a heightened awareness of this complication. In all of the reported cases, the patients required hospitalization because of the severity of symptoms and attempts to exclude other possible diseases.³⁶

POSSIBLY DUE TO BRADYKININ

Several theories have been proposed to explain how visceral angioedema is induced by ACE inhibitors. The possible mechanisms that have been described include the following:

• The accumulation of bradykinin and substance P secondary to the effect of the ACE inhibitor, which may lead to the inflammatory response, therefore increasing permeability of the vascular compartment
• Deficiency of complement and the enzymes carboxypeptidase N and alpha-1 antitrypsin
• An antibody-antigen reaction³⁷
• Hormones such as estrogen and progesterone (suggested by the greater number of women represented³⁸)
• Contrast media used for imaging³⁹
• Genetic predisposition
• Inflammation due to acute-phase proteins
• C1-inhibitor deficiency or dysfunction (however, the levels of C1/C4 and the C1-esterase inhibitor functional activity usually are normal^2,10,40).

Many other theories are being explored.^{11,12,38,41–53}

The most plausible mechanism is an increase in the levels of bradykinin and its metabolites.⁴⁵ The absence of ACE can lead to breakdown of bradykinin to des-Arg bradykinin via the minor pathway, which can lead to more pronounced vasodilation and vascular permeability.^54,55 During an acute attack of angioedema secondary to ACE inhibition, the bradykinin concentration can increase to more than 10 times the normal level.⁵⁶

Moreover, C-reactive protein levels were higher (mean 4.42 mg/dL ± 0.15 mg/dL) in patients with ACE-inhibitor-induced angioedema than in those with other causes of angioedema (P < .0001).⁵² The patients taking ACE inhibitors without any previous angioedema had normal C-reactive protein levels (0.39 mg/dL ± 0.1 mg/dL).⁵²

INCIDENCE RATES

In our review of the literature, all of the patients were taking an ACE inhibitor, and some were taking both an ACE inhibitor and an angiotensin-receptor blocker (ARB).

Initially, the incidence rate of angioedema was thought to be 0.1% to 0.2%, but recently the Omapatrilat Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) trial had more than 12,000 patients on enalapril and reported the incidence of angioedema to be 0.68%,⁵⁷ with a higher risk in women than in men (0.84% vs 0.54%)⁵⁸ and a relative risk of 3.03 for blacks compared with whites.⁵⁹

Even though ARBs seem to be safer, angioedema can recur in up to one-third of patients who switch from an ACE inhibitor to an ARB.^60–63

Moreover, one study in the United States found that the frequency of hospital admission of patients with angioedema increased from 8,839 per year in 1998 to 11,925 in 2005, and the cost was estimated to be close to $123 million in 2005.⁶⁴

Interestingly, when angioedema involved the face, it developed within the first week in 60% of cases,⁶⁵ whereas when visceral angioedema developed, it did so within the first week in 59% of cases. Therefore, the timing of the onset is similar regardless of the body area involved.

Smokers who developed ACE-inhibitor-induced cough had a higher risk of ACE-inhibitor-induced angioedema in a retrospective cohort study by Morimoto,⁶⁶ but no relationship to the area of involvement was made.

ON IMAGING, A THICKENED BOWEL WALL

Computed tomography can reveal bowel edema and ascites more reliably than plain radiography or barium studies. Edema thickens the bowel wall, with increased contrast enhancement that makes mesenteric vessels show up on the study. In some instances edema is so significant that edematous submucosa can be differentiated from the serosa due to impressive thickening of the mucosal wall.^15,16 Oral contrast can be seen in the middle of the lumen, giving it a target-sign appearance. Edema of the small bowel and ascites can lead to fluid sequestration in the abdomen, resulting in a presentation with shock.⁶⁷

Magnetic resonance imaging can be even more useful in identifying gastrointestinal angioedema, but it would not be cost-effective, and based on our study, CT and ultrasonography of the abdomen were diagnostic in most cases.

AVOIDING UNNECESSARY TESTING

Hemodynamic instability and abdominal pain usually trigger a surgical consult and a more extensive workup, but with a good clinical approach, unnecessary testing and invasive diagnostic procedures can be avoided under the right circumstances.

Numerous surgical procedures have been reported in patients presenting with visceral angioedema secondary to ACE inhibitors.⁶⁷ Although a thorough history and physical examination can give us a clue in the diagnosis of drug-induced gastrointestinal angioedema, CT is extremely helpful, as it shows dilated loops, thickened mucosal folds, perihepatic fluid, ascites, mesenteric edema, and a “doughnut” or “stacked coin” appearance.^17,68

So far, there have been only two reports of angioedema of the stomach (the case reported by Shahzad et al¹⁰ and the current report). Angioedema can affect any visceral organ, but we usually see involvement of the jejunum followed by the ileum and duodenum.⁴⁰

FINDINGS ON ENDOSCOPY

Usually, endoscopic examination of the upper and lower gastrointestinal tract does not reveal any specific pathology, but endoscopy and biopsy can rule out other causes of abdominal pain, such as Crohn disease, ulcerative colitis, infection, malignancy, granuloma, and vasculitis. Also, hereditary or acquired C1-esterase deficiency and other autoimmune disorders should be considered in the workup.^18,69 In the reported cases, endoscopy revealed petechial bleeding with generalized edema.¹⁹

Biopsy often demonstrates an expanded edematous submucosal layer with inflammatory cell infiltration and protrusion of the proper muscular layer into the submucosal layer.¹⁵ A proper muscular layer and an edematous submucosal layer can produce edema so severe as to obstruct the intestine.¹⁵

Ultrasonography or CT provides essential information as to location, structure, and size, and it rules out other diagnoses. Therefore, consideration should be given to noninvasive imaging studies and laboratory testing (C1-esterase inhibitor, complement, antinuclear antibody, complete metabolic panel, complete blood cell count) before resorting to endoscopy or exploratory laparotomy.^20,70 In three case reports,^29,30,32 abdominal ultrasonography did not show any thickening of the small-bowel wall. Several cases have been diagnosed with the help of endoscopy.

Symptoms usually resolve when the ACE inhibitor is stopped

There is no standard treatment for ACE-inhibitor-induced visceral angioedema. In most patients, stopping the drug, giving nothing by mouth, and giving intravenous fluids to prevent dehydration are sufficient. Symptoms usually resolve within 48 hours.

In several case reports, fresh-frozen plasma was used to increase the levels of kininase II, which can degrade high levels of bradykinin.^51,71,72 However, no randomized controlled trial of fresh-frozen plasma for ACE-inhibitor-induced angioedema has been published.

Drugs for hereditary angioedema—eg, recombinant C1-INH, the kallikrein inhibitor ecallantide (Kalbitor), and the BKR-2-antagonist icatibant (Firazyr)⁷³—have not been prospectively studied in gastrointestinal angioedema associated with ACE inhibitors. Icatibant has been shown to be effective in the treatment of hereditary angioedema and could be promising in treating angioedema secondary to ACE inhibitors.⁸ Rosenberg et al²¹ described a patient who was on prednisone when she developed intestinal angioedema, thus calling into question the efficacy of steroids in the treatment of visceral angioedema.

RAISING AWARENESS

More than 40 million patients are currently taking ACE inhibitors or ARBs.⁹ Therefore, we suggest that patients with a known history of angioedema in response to these drugs should wear an identification bracelet to increase awareness and to prevent recurrence of angioedema.

A 57-year-old black woman presented to the emergency department with severe, dull abdominal pain associated with nonbilious vomiting and nausea. She had diabetes mellitus and hypertension, for which she had been taking metformin (Glucophage) 500 mg twice a day and lisinopril (available as Prinivil and Zestril) 20 mg daily for the last 4 years.

Multiple admissions in the past 4 years

The patient started taking lisinopril 10 mg daily in 2005, and she presented to her medical provider 2 weeks later with abdominal discomfort. Colonoscopy was performed, which revealed a benign polyp. She continued taking her medications, including lisinopril.

She continued to occasionally have abdominal pain of variable severity, but it was tolerable until 6 months later, when she presented to the emergency department with severe recurrent abdominal pain.

In view of the clinical picture, her physicians decided to treat her for small bowel obstruction, and an exploratory laparotomy was performed. The surgeons noted that she had moderate ascites, adhesions on the omentum, and a thickened high loop of the small bowel that was unequivocally viable and hyperemic, with thickening of the mesentery. Ascitic fluid was evacuated, adhesions were lysed, and the abdomen was closed. She was discharged with the same medications, including lisinopril; the dose was subsequently increased for better control of her hypertension.

The woman was admitted three more times within the same year for the same symptoms and underwent multiple workups for pancreatitis, gastritis, small-bowel obstruction, and other common gastrointestinal diseases.

Present admission

On review of systems, she denied any dry cough, weight loss or gain, food allergies, new medications, or hematochezia.

On physical examination, she had hypoactive bowel sounds and diffuse tenderness with guarding around the epigastric area.

Laboratory tests did not reveal any abnormalities; in particular, her C1 esterase concentration was normal. Stool studies were negative for infectious diseases.

Plain radiography of the abdomen showed a nonobstructive bowel-gas pattern.

She was diagnosed with gastrointestinal angioedema secondary to angiotensin-converting enzyme (ACE) inhibitor therapy. Her lisinopril was discontinued, and the symptoms resolved completely in 24 hours. On follow-up 8 weeks and 16 months later, her symptoms had not returned.

A RARE COMPLICATION OF ACE-INHIBITOR THERAPY

Angioedema occurs in 0.1% to 0.7% of patients taking ACE inhibitors, and it can affect about 1 of 2,500 patients during the first week of exposure.^1–3 It usually manifests as swelling of the face, tongue, and lips, and in rare cases, the gastrointestinal wall. Thus, visceral angioedema is a rare complication of ACE-inhibitor therapy.

Because angioedema is less obvious when it involves abdominal organs, it presents a diagnostic challenge. It is placed lower in the differential diagnosis, as other, more common, and occasionally more high-risk medical conditions are generally considered first. Most of the time, the diagnosis is missed. Some physicians may not be aware of this problem, since only a few case reports have been published. Nevertheless, this potential complication needs to be considered when any patient receiving ACE inhibitors for treatment of hypertension, myocardial infarction, heart failure, or diabetic nephropathy presents with diffuse abdominal pain, diarrhea, or edema of the upper airways.^4–8

If a high level of suspicion is applied along with good clinical judgment, then hospitalizations, unnecessary procedures, patient discomfort, and unnecessary health care costs can be prevented.

A MEDLINE SEARCH

To investigate the characteristics associated with this unusual presentation, including the time of symptom onset, the types of symptoms, and the diagnostic studies performed on the patients with visceral angioedema, we performed a MEDLINE search to identify case reports and case series published in English from 1980 to 2010 on the topic of abdominal or visceral angioedema. The search terms used were “visceral,” “intestinal angioedema,” “ACE-inhibitor side effects,” and the names of various ACE inhibitors.

Pertinent articles were identified, and clinical characteristics were collected, including demographics, onset of symptoms, the drug’s name, and others. In our summary below, data are presented as the mean and standard deviation for continuous variables and percentages for categorical variables.

SUMMARY OF REPORTED CASES

Our search revealed 27 reported cases of visceral angioedema associated with ACE inhibitors (a table summarizing our findings is available).^9–34 The drug most often involved was lisinopril (11 cases), followed by enalapril (Vasotec) (8 cases).

Twenty-three (82%) of the cases were in women. The mean age of the patients was 49.5 ± 12.2 years (range 29–77 years); the mean age was 46.7 ± 11.7 years in women and 57 ± 13 years in men. Unfortunately, the race and ethnicity of the patients was documented in only some cases.

In 15 (54%) of the cases, the patient presented to a physician or emergency department within 72 hours (41.1 ± 17.4) of starting therapy, and in 8 cases the patient presented between 2 weeks and 18 months.

In 10 cases (including the case we are reporting here), the patients were kept on ACE inhibitors from 2 to 9 years after the initial presentation, as the diagnosis was missed.^{9,12,14,18,20,31,32} In 2 cases, the dose of the ACE inhibitor had been increased after the patient presented with the abdominal pain.

All of the patients were hospitalized for further diagnostic workup.

As for the presenting symptoms, all the patients had abdominal pain, 24 (86%) had emesis, 14 (50%) had diarrhea, and 20 (71%) had ascites. Laboratory results were mostly nonspecific. Twelve (44%) of the patients had leukocytosis. The C1 esterase inhibitor concentration was measured in 18 patients, and the results were normal in all of them.

Twenty-four (86%) of the patients underwent abdominal and pelvic CT or ultrasonography as part of the initial diagnostic evaluation, and intestinal wall-thickening was found in 21 (87.5%) of them.

Either surgery or gastrointestinal biopsy was performed in 16 (57%) of the patients; the surgical procedures included 2 cholecystectomies and 1 bone marrow biopsy. Only 1 case was diagnosed on the basis of clinical suspicion and abdominal radiographs alone.

The combination of intestinal and stomach angioedema was found in only 2 cases.

Two patients were kept on an ACE inhibitor in spite of symptoms and intestinal wall edema that showed a migratory pattern on imaging after chronic exposure.

The thickening involved the jejunum in 14 patients (50%), the ileum in 8 (29%), the duodenum in 5 (18%), the stomach in 2, and the sigmoid colon in 1.

In 12 cases (43%), visceral angioedema and its symptoms resolved within 48 hours of stopping the ACE inhibitor.

A DIAGNOSIS TO KEEP IN MIND

As we have seen, the diagnosis of visceral angioedema needs to be kept in mind when a patient—especially a middle-aged woman—taking an ACE inhibitor presents with abdominal pain, vomiting, diarrhea, leukocytosis, ascites, and wall-thickening of the small bowel on imaging studies.^9,35,36

The diagnosis is hard to establish, and in the interim the patient may undergo invasive and unnecessary procedures, which can be avoided by a heightened awareness of this complication. In all of the reported cases, the patients required hospitalization because of the severity of symptoms and attempts to exclude other possible diseases.³⁶

POSSIBLY DUE TO BRADYKININ

Several theories have been proposed to explain how visceral angioedema is induced by ACE inhibitors. The possible mechanisms that have been described include the following:

• The accumulation of bradykinin and substance P secondary to the effect of the ACE inhibitor, which may lead to the inflammatory response, therefore increasing permeability of the vascular compartment
• Deficiency of complement and the enzymes carboxypeptidase N and alpha-1 antitrypsin
• An antibody-antigen reaction³⁷
• Hormones such as estrogen and progesterone (suggested by the greater number of women represented³⁸)
• Contrast media used for imaging³⁹
• Genetic predisposition
• Inflammation due to acute-phase proteins
• C1-inhibitor deficiency or dysfunction (however, the levels of C1/C4 and the C1-esterase inhibitor functional activity usually are normal^2,10,40).

Many other theories are being explored.^{11,12,38,41–53}

The most plausible mechanism is an increase in the levels of bradykinin and its metabolites.⁴⁵ The absence of ACE can lead to breakdown of bradykinin to des-Arg bradykinin via the minor pathway, which can lead to more pronounced vasodilation and vascular permeability.^54,55 During an acute attack of angioedema secondary to ACE inhibition, the bradykinin concentration can increase to more than 10 times the normal level.⁵⁶

Moreover, C-reactive protein levels were higher (mean 4.42 mg/dL ± 0.15 mg/dL) in patients with ACE-inhibitor-induced angioedema than in those with other causes of angioedema (P < .0001).⁵² The patients taking ACE inhibitors without any previous angioedema had normal C-reactive protein levels (0.39 mg/dL ± 0.1 mg/dL).⁵²

INCIDENCE RATES

In our review of the literature, all of the patients were taking an ACE inhibitor, and some were taking both an ACE inhibitor and an angiotensin-receptor blocker (ARB).

Initially, the incidence rate of angioedema was thought to be 0.1% to 0.2%, but recently the Omapatrilat Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) trial had more than 12,000 patients on enalapril and reported the incidence of angioedema to be 0.68%,⁵⁷ with a higher risk in women than in men (0.84% vs 0.54%)⁵⁸ and a relative risk of 3.03 for blacks compared with whites.⁵⁹

Even though ARBs seem to be safer, angioedema can recur in up to one-third of patients who switch from an ACE inhibitor to an ARB.^60–63

Moreover, one study in the United States found that the frequency of hospital admission of patients with angioedema increased from 8,839 per year in 1998 to 11,925 in 2005, and the cost was estimated to be close to $123 million in 2005.⁶⁴

Interestingly, when angioedema involved the face, it developed within the first week in 60% of cases,⁶⁵ whereas when visceral angioedema developed, it did so within the first week in 59% of cases. Therefore, the timing of the onset is similar regardless of the body area involved.

Smokers who developed ACE-inhibitor-induced cough had a higher risk of ACE-inhibitor-induced angioedema in a retrospective cohort study by Morimoto,⁶⁶ but no relationship to the area of involvement was made.

ON IMAGING, A THICKENED BOWEL WALL

Computed tomography can reveal bowel edema and ascites more reliably than plain radiography or barium studies. Edema thickens the bowel wall, with increased contrast enhancement that makes mesenteric vessels show up on the study. In some instances edema is so significant that edematous submucosa can be differentiated from the serosa due to impressive thickening of the mucosal wall.^15,16 Oral contrast can be seen in the middle of the lumen, giving it a target-sign appearance. Edema of the small bowel and ascites can lead to fluid sequestration in the abdomen, resulting in a presentation with shock.⁶⁷

Magnetic resonance imaging can be even more useful in identifying gastrointestinal angioedema, but it would not be cost-effective, and based on our study, CT and ultrasonography of the abdomen were diagnostic in most cases.

AVOIDING UNNECESSARY TESTING

Hemodynamic instability and abdominal pain usually trigger a surgical consult and a more extensive workup, but with a good clinical approach, unnecessary testing and invasive diagnostic procedures can be avoided under the right circumstances.

Numerous surgical procedures have been reported in patients presenting with visceral angioedema secondary to ACE inhibitors.⁶⁷ Although a thorough history and physical examination can give us a clue in the diagnosis of drug-induced gastrointestinal angioedema, CT is extremely helpful, as it shows dilated loops, thickened mucosal folds, perihepatic fluid, ascites, mesenteric edema, and a “doughnut” or “stacked coin” appearance.^17,68

So far, there have been only two reports of angioedema of the stomach (the case reported by Shahzad et al¹⁰ and the current report). Angioedema can affect any visceral organ, but we usually see involvement of the jejunum followed by the ileum and duodenum.⁴⁰

FINDINGS ON ENDOSCOPY

Usually, endoscopic examination of the upper and lower gastrointestinal tract does not reveal any specific pathology, but endoscopy and biopsy can rule out other causes of abdominal pain, such as Crohn disease, ulcerative colitis, infection, malignancy, granuloma, and vasculitis. Also, hereditary or acquired C1-esterase deficiency and other autoimmune disorders should be considered in the workup.^18,69 In the reported cases, endoscopy revealed petechial bleeding with generalized edema.¹⁹

Biopsy often demonstrates an expanded edematous submucosal layer with inflammatory cell infiltration and protrusion of the proper muscular layer into the submucosal layer.¹⁵ A proper muscular layer and an edematous submucosal layer can produce edema so severe as to obstruct the intestine.¹⁵

Ultrasonography or CT provides essential information as to location, structure, and size, and it rules out other diagnoses. Therefore, consideration should be given to noninvasive imaging studies and laboratory testing (C1-esterase inhibitor, complement, antinuclear antibody, complete metabolic panel, complete blood cell count) before resorting to endoscopy or exploratory laparotomy.^20,70 In three case reports,^29,30,32 abdominal ultrasonography did not show any thickening of the small-bowel wall. Several cases have been diagnosed with the help of endoscopy.

Symptoms usually resolve when the ACE inhibitor is stopped

There is no standard treatment for ACE-inhibitor-induced visceral angioedema. In most patients, stopping the drug, giving nothing by mouth, and giving intravenous fluids to prevent dehydration are sufficient. Symptoms usually resolve within 48 hours.

In several case reports, fresh-frozen plasma was used to increase the levels of kininase II, which can degrade high levels of bradykinin.^51,71,72 However, no randomized controlled trial of fresh-frozen plasma for ACE-inhibitor-induced angioedema has been published.

Drugs for hereditary angioedema—eg, recombinant C1-INH, the kallikrein inhibitor ecallantide (Kalbitor), and the BKR-2-antagonist icatibant (Firazyr)⁷³—have not been prospectively studied in gastrointestinal angioedema associated with ACE inhibitors. Icatibant has been shown to be effective in the treatment of hereditary angioedema and could be promising in treating angioedema secondary to ACE inhibitors.⁸ Rosenberg et al²¹ described a patient who was on prednisone when she developed intestinal angioedema, thus calling into question the efficacy of steroids in the treatment of visceral angioedema.

RAISING AWARENESS

More than 40 million patients are currently taking ACE inhibitors or ARBs.⁹ Therefore, we suggest that patients with a known history of angioedema in response to these drugs should wear an identification bracelet to increase awareness and to prevent recurrence of angioedema.

A 57-year-old black woman presented to the emergency department with severe, dull abdominal pain associated with nonbilious vomiting and nausea. She had diabetes mellitus and hypertension, for which she had been taking metformin (Glucophage) 500 mg twice a day and lisinopril (available as Prinivil and Zestril) 20 mg daily for the last 4 years.

Multiple admissions in the past 4 years

The patient started taking lisinopril 10 mg daily in 2005, and she presented to her medical provider 2 weeks later with abdominal discomfort. Colonoscopy was performed, which revealed a benign polyp. She continued taking her medications, including lisinopril.

She continued to occasionally have abdominal pain of variable severity, but it was tolerable until 6 months later, when she presented to the emergency department with severe recurrent abdominal pain.

In view of the clinical picture, her physicians decided to treat her for small bowel obstruction, and an exploratory laparotomy was performed. The surgeons noted that she had moderate ascites, adhesions on the omentum, and a thickened high loop of the small bowel that was unequivocally viable and hyperemic, with thickening of the mesentery. Ascitic fluid was evacuated, adhesions were lysed, and the abdomen was closed. She was discharged with the same medications, including lisinopril; the dose was subsequently increased for better control of her hypertension.

The woman was admitted three more times within the same year for the same symptoms and underwent multiple workups for pancreatitis, gastritis, small-bowel obstruction, and other common gastrointestinal diseases.

Present admission

On review of systems, she denied any dry cough, weight loss or gain, food allergies, new medications, or hematochezia.

On physical examination, she had hypoactive bowel sounds and diffuse tenderness with guarding around the epigastric area.

Laboratory tests did not reveal any abnormalities; in particular, her C1 esterase concentration was normal. Stool studies were negative for infectious diseases.

Plain radiography of the abdomen showed a nonobstructive bowel-gas pattern.

She was diagnosed with gastrointestinal angioedema secondary to angiotensin-converting enzyme (ACE) inhibitor therapy. Her lisinopril was discontinued, and the symptoms resolved completely in 24 hours. On follow-up 8 weeks and 16 months later, her symptoms had not returned.

A RARE COMPLICATION OF ACE-INHIBITOR THERAPY

Angioedema occurs in 0.1% to 0.7% of patients taking ACE inhibitors, and it can affect about 1 of 2,500 patients during the first week of exposure.^1–3 It usually manifests as swelling of the face, tongue, and lips, and in rare cases, the gastrointestinal wall. Thus, visceral angioedema is a rare complication of ACE-inhibitor therapy.

Because angioedema is less obvious when it involves abdominal organs, it presents a diagnostic challenge. It is placed lower in the differential diagnosis, as other, more common, and occasionally more high-risk medical conditions are generally considered first. Most of the time, the diagnosis is missed. Some physicians may not be aware of this problem, since only a few case reports have been published. Nevertheless, this potential complication needs to be considered when any patient receiving ACE inhibitors for treatment of hypertension, myocardial infarction, heart failure, or diabetic nephropathy presents with diffuse abdominal pain, diarrhea, or edema of the upper airways.^4–8

If a high level of suspicion is applied along with good clinical judgment, then hospitalizations, unnecessary procedures, patient discomfort, and unnecessary health care costs can be prevented.

A MEDLINE SEARCH

To investigate the characteristics associated with this unusual presentation, including the time of symptom onset, the types of symptoms, and the diagnostic studies performed on the patients with visceral angioedema, we performed a MEDLINE search to identify case reports and case series published in English from 1980 to 2010 on the topic of abdominal or visceral angioedema. The search terms used were “visceral,” “intestinal angioedema,” “ACE-inhibitor side effects,” and the names of various ACE inhibitors.

Pertinent articles were identified, and clinical characteristics were collected, including demographics, onset of symptoms, the drug’s name, and others. In our summary below, data are presented as the mean and standard deviation for continuous variables and percentages for categorical variables.

SUMMARY OF REPORTED CASES

Our search revealed 27 reported cases of visceral angioedema associated with ACE inhibitors (a table summarizing our findings is available).^9–34 The drug most often involved was lisinopril (11 cases), followed by enalapril (Vasotec) (8 cases).

Twenty-three (82%) of the cases were in women. The mean age of the patients was 49.5 ± 12.2 years (range 29–77 years); the mean age was 46.7 ± 11.7 years in women and 57 ± 13 years in men. Unfortunately, the race and ethnicity of the patients was documented in only some cases.

In 15 (54%) of the cases, the patient presented to a physician or emergency department within 72 hours (41.1 ± 17.4) of starting therapy, and in 8 cases the patient presented between 2 weeks and 18 months.

In 10 cases (including the case we are reporting here), the patients were kept on ACE inhibitors from 2 to 9 years after the initial presentation, as the diagnosis was missed.^{9,12,14,18,20,31,32} In 2 cases, the dose of the ACE inhibitor had been increased after the patient presented with the abdominal pain.

All of the patients were hospitalized for further diagnostic workup.

As for the presenting symptoms, all the patients had abdominal pain, 24 (86%) had emesis, 14 (50%) had diarrhea, and 20 (71%) had ascites. Laboratory results were mostly nonspecific. Twelve (44%) of the patients had leukocytosis. The C1 esterase inhibitor concentration was measured in 18 patients, and the results were normal in all of them.

Twenty-four (86%) of the patients underwent abdominal and pelvic CT or ultrasonography as part of the initial diagnostic evaluation, and intestinal wall-thickening was found in 21 (87.5%) of them.

Either surgery or gastrointestinal biopsy was performed in 16 (57%) of the patients; the surgical procedures included 2 cholecystectomies and 1 bone marrow biopsy. Only 1 case was diagnosed on the basis of clinical suspicion and abdominal radiographs alone.

The combination of intestinal and stomach angioedema was found in only 2 cases.

Two patients were kept on an ACE inhibitor in spite of symptoms and intestinal wall edema that showed a migratory pattern on imaging after chronic exposure.

The thickening involved the jejunum in 14 patients (50%), the ileum in 8 (29%), the duodenum in 5 (18%), the stomach in 2, and the sigmoid colon in 1.

In 12 cases (43%), visceral angioedema and its symptoms resolved within 48 hours of stopping the ACE inhibitor.

A DIAGNOSIS TO KEEP IN MIND

As we have seen, the diagnosis of visceral angioedema needs to be kept in mind when a patient—especially a middle-aged woman—taking an ACE inhibitor presents with abdominal pain, vomiting, diarrhea, leukocytosis, ascites, and wall-thickening of the small bowel on imaging studies.^9,35,36

The diagnosis is hard to establish, and in the interim the patient may undergo invasive and unnecessary procedures, which can be avoided by a heightened awareness of this complication. In all of the reported cases, the patients required hospitalization because of the severity of symptoms and attempts to exclude other possible diseases.³⁶

POSSIBLY DUE TO BRADYKININ

Several theories have been proposed to explain how visceral angioedema is induced by ACE inhibitors. The possible mechanisms that have been described include the following:

• The accumulation of bradykinin and substance P secondary to the effect of the ACE inhibitor, which may lead to the inflammatory response, therefore increasing permeability of the vascular compartment
• Deficiency of complement and the enzymes carboxypeptidase N and alpha-1 antitrypsin
• An antibody-antigen reaction³⁷
• Hormones such as estrogen and progesterone (suggested by the greater number of women represented³⁸)
• Contrast media used for imaging³⁹
• Genetic predisposition
• Inflammation due to acute-phase proteins
• C1-inhibitor deficiency or dysfunction (however, the levels of C1/C4 and the C1-esterase inhibitor functional activity usually are normal^2,10,40).

Many other theories are being explored.^{11,12,38,41–53}

The most plausible mechanism is an increase in the levels of bradykinin and its metabolites.⁴⁵ The absence of ACE can lead to breakdown of bradykinin to des-Arg bradykinin via the minor pathway, which can lead to more pronounced vasodilation and vascular permeability.^54,55 During an acute attack of angioedema secondary to ACE inhibition, the bradykinin concentration can increase to more than 10 times the normal level.⁵⁶

Moreover, C-reactive protein levels were higher (mean 4.42 mg/dL ± 0.15 mg/dL) in patients with ACE-inhibitor-induced angioedema than in those with other causes of angioedema (P < .0001).⁵² The patients taking ACE inhibitors without any previous angioedema had normal C-reactive protein levels (0.39 mg/dL ± 0.1 mg/dL).⁵²

INCIDENCE RATES

In our review of the literature, all of the patients were taking an ACE inhibitor, and some were taking both an ACE inhibitor and an angiotensin-receptor blocker (ARB).

Initially, the incidence rate of angioedema was thought to be 0.1% to 0.2%, but recently the Omapatrilat Cardiovascular Treatment Assessment vs Enalapril (OCTAVE) trial had more than 12,000 patients on enalapril and reported the incidence of angioedema to be 0.68%,⁵⁷ with a higher risk in women than in men (0.84% vs 0.54%)⁵⁸ and a relative risk of 3.03 for blacks compared with whites.⁵⁹

Even though ARBs seem to be safer, angioedema can recur in up to one-third of patients who switch from an ACE inhibitor to an ARB.^60–63

Moreover, one study in the United States found that the frequency of hospital admission of patients with angioedema increased from 8,839 per year in 1998 to 11,925 in 2005, and the cost was estimated to be close to $123 million in 2005.⁶⁴

Interestingly, when angioedema involved the face, it developed within the first week in 60% of cases,⁶⁵ whereas when visceral angioedema developed, it did so within the first week in 59% of cases. Therefore, the timing of the onset is similar regardless of the body area involved.

Smokers who developed ACE-inhibitor-induced cough had a higher risk of ACE-inhibitor-induced angioedema in a retrospective cohort study by Morimoto,⁶⁶ but no relationship to the area of involvement was made.

ON IMAGING, A THICKENED BOWEL WALL

Computed tomography can reveal bowel edema and ascites more reliably than plain radiography or barium studies. Edema thickens the bowel wall, with increased contrast enhancement that makes mesenteric vessels show up on the study. In some instances edema is so significant that edematous submucosa can be differentiated from the serosa due to impressive thickening of the mucosal wall.^15,16 Oral contrast can be seen in the middle of the lumen, giving it a target-sign appearance. Edema of the small bowel and ascites can lead to fluid sequestration in the abdomen, resulting in a presentation with shock.⁶⁷

Magnetic resonance imaging can be even more useful in identifying gastrointestinal angioedema, but it would not be cost-effective, and based on our study, CT and ultrasonography of the abdomen were diagnostic in most cases.

AVOIDING UNNECESSARY TESTING

Hemodynamic instability and abdominal pain usually trigger a surgical consult and a more extensive workup, but with a good clinical approach, unnecessary testing and invasive diagnostic procedures can be avoided under the right circumstances.

Numerous surgical procedures have been reported in patients presenting with visceral angioedema secondary to ACE inhibitors.⁶⁷ Although a thorough history and physical examination can give us a clue in the diagnosis of drug-induced gastrointestinal angioedema, CT is extremely helpful, as it shows dilated loops, thickened mucosal folds, perihepatic fluid, ascites, mesenteric edema, and a “doughnut” or “stacked coin” appearance.^17,68

So far, there have been only two reports of angioedema of the stomach (the case reported by Shahzad et al¹⁰ and the current report). Angioedema can affect any visceral organ, but we usually see involvement of the jejunum followed by the ileum and duodenum.⁴⁰

FINDINGS ON ENDOSCOPY

Usually, endoscopic examination of the upper and lower gastrointestinal tract does not reveal any specific pathology, but endoscopy and biopsy can rule out other causes of abdominal pain, such as Crohn disease, ulcerative colitis, infection, malignancy, granuloma, and vasculitis. Also, hereditary or acquired C1-esterase deficiency and other autoimmune disorders should be considered in the workup.^18,69 In the reported cases, endoscopy revealed petechial bleeding with generalized edema.¹⁹

Biopsy often demonstrates an expanded edematous submucosal layer with inflammatory cell infiltration and protrusion of the proper muscular layer into the submucosal layer.¹⁵ A proper muscular layer and an edematous submucosal layer can produce edema so severe as to obstruct the intestine.¹⁵

Ultrasonography or CT provides essential information as to location, structure, and size, and it rules out other diagnoses. Therefore, consideration should be given to noninvasive imaging studies and laboratory testing (C1-esterase inhibitor, complement, antinuclear antibody, complete metabolic panel, complete blood cell count) before resorting to endoscopy or exploratory laparotomy.^20,70 In three case reports,^29,30,32 abdominal ultrasonography did not show any thickening of the small-bowel wall. Several cases have been diagnosed with the help of endoscopy.

Symptoms usually resolve when the ACE inhibitor is stopped

There is no standard treatment for ACE-inhibitor-induced visceral angioedema. In most patients, stopping the drug, giving nothing by mouth, and giving intravenous fluids to prevent dehydration are sufficient. Symptoms usually resolve within 48 hours.

In several case reports, fresh-frozen plasma was used to increase the levels of kininase II, which can degrade high levels of bradykinin.^51,71,72 However, no randomized controlled trial of fresh-frozen plasma for ACE-inhibitor-induced angioedema has been published.

Drugs for hereditary angioedema—eg, recombinant C1-INH, the kallikrein inhibitor ecallantide (Kalbitor), and the BKR-2-antagonist icatibant (Firazyr)⁷³—have not been prospectively studied in gastrointestinal angioedema associated with ACE inhibitors. Icatibant has been shown to be effective in the treatment of hereditary angioedema and could be promising in treating angioedema secondary to ACE inhibitors.⁸ Rosenberg et al²¹ described a patient who was on prednisone when she developed intestinal angioedema, thus calling into question the efficacy of steroids in the treatment of visceral angioedema.

RAISING AWARENESS

More than 40 million patients are currently taking ACE inhibitors or ARBs.⁹ Therefore, we suggest that patients with a known history of angioedema in response to these drugs should wear an identification bracelet to increase awareness and to prevent recurrence of angioedema.