THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.

THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.

THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.

CASE 1

A 13-month-old boy who was recently adopted from Ethiopia presented to a primary care physician with a 3-week history of bloody diarrhea accompanied by flatulence and bloating. Stool cultures were positive for Campylobacter and Shigella. He was prescribed azithromycin but saw only moderate improvement. He was then referred to the Infectious Diseases Department. Neonatal, pregnancy, and immunization histories were unknown and a review of systems was unremarkable. On exam, the child looked well; he weighed 9.6 kg (15th percentile), was 69.5 cm long (<3rd percentile), and his head circumference was 45 cm (10th percentile). Head and neck, cardiorespiratory, and abdominal examinations were unremarkable.

A complete blood count (CBC) showed an elevated white blood cell (WBC) count of 26 x 10⁹/L (normal: 4-10 x 10⁹/L) with predominant eosinophilia (10.4 x 10⁹/L or 40.1% of WBCs; normal: <0.45 x 10⁹/L or 0%-8%). Hemoglobin and platelets were within normal limits. Stool testing for ova and parasites showed Strongyloides stercoralis larvae. Strongyloides serology was negative and Filaria serology was equivocal.

CASE 2

A 15-year-old boy was assessed for a 3-week history of fever and eosinophilia. He had enlarged cervical lymph nodes, a new rash, and had lost 4 pounds. He denied gastrointestinal symptoms, dyspnea, headaches, or chest pain. His past medical and family histories were unremarkable and he reported no drug use or allergies. He had traveled to Cuba with his family for 15 days 3 months prior to presentation. He recalled diarrhea while traveling, which resolved spontaneously. He and his family had traveled “off the beaten track,” eating foods prepared at local establishments and swimming in local rivers. He received pre-travel immunizations.

On examination, he appeared unwell, though his vital signs were normal. He had diffuse lymphadenopathy and a petechial rash on his chest, back, upper buttocks, legs, and feet. Cardiorespiratory and abdominal examinations were unremarkable. A CBC revealed an elevated WBC count of 76.9 x 10⁹/L with predominant eosinophilia (71.5 x 10⁹/L or 92% of WBCs). Hemoglobin, platelets, electrolytes, and liver function tests were normal. The patient was referred to a tertiary care center and was admitted to the hospital. Stool testing for ova and parasites, as well as serology for parasitic infections, was negative. A bone marrow aspiration and biopsy were performed and revealed the diagnosis of acute lymphoblastic leukemia (ALL).

These 2 cases highlight how the presentation of eosinophilia can vary and how important it is to maintain a broad differential diagnosis (TABLE 1^1-4). Causes of eosinophilia are numerous and can be divided into 3 categories: primary, secondary, and idiopathic.^1,5 Hematologic malignancy, where eosinophilia is clonal, is an example of a primary etiology. Causes of secondary eosinophilia include infectious diseases, drugs (TABLE 2⁵), autoimmune disorders, and allergic conditions. Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage. Dermatologic, pulmonary, gastro­intestinal, and cardiac involvement is most common.²

Eosinophilia associated with parasitic infection

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia, with eosinophilia occurring during tissue migration or penetration.^1,3

Schistosomiasis is a chronic parasitic infection of the human vascular system. It is transmitted by contact with contaminated fresh water, where cercariae penetrate the skin. High prevalence areas include Africa and Southeast Asia. Acute infection can result in Katayama fever—a febrile illness with prominent eosinophilia that occurs 4 to 7 weeks after exposure.⁴ Diagnosis is primarily clinical with appropriate epidemiology, as serology may be negative early in infection. Praziquantel is the treatment of choice, though dosing varies by species, so expert consultation should be considered.

Soil-transmitted helminths, such as Ascaris (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancyclostoma duodenale and Necator americanus), can also cause eosinophilia during larval tissue migration. Following infection by ingestion or skin penetration, an acute respiratory illness, termed Löffler’s syndrome, can develop with associated eosinophilia.¹ Once the helminths reach the adult stage, eosinophilia subsides. Patients are most commonly treated with albendazole 400 mg orally for 3 days.⁴

Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage.Fascioliasis is common in sheep-rearing areas. Humans are infected through ingestion of aquatic plants (eg, watercress). Parasitic migration through the duodenal wall and liver parenchyma can lead to fever, right upper quadrant pain, and eosinophilia. The incubation period is 6 to 12 weeks. Diagnosis during acute infection is by serology.⁴

Filarial infections, eg lymphatic filariasis, loiasis, and onchocerciasis, can also cause eosinophilia. The rise in eosinophils can be triggered by either the adult worms or circulating microfilariae.⁴ Treatment of fascioliasis and filarial infections varies and expert consultation is recommended.

Eosinophilia associated with primary hematologic malignancy

Eosinophilia is a rare presentation of hematologic malignancy. Acute myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, and myeloproliferative disorders have all been associated with eosinophilia. Hepatosplenomegaly, generalized lymphadenopathy, and cytopenias in other cell lines are often noted. Also, the degree of eosinophilia is often more pronounced (>5 x 10⁹/L). Patients with suspected hematologic malignancy should be urgently referred for expert consultation.⁵

Consider the following approach in the assessment of patients with eosinophilia seen in the ambulatory care setting. Inpatients or patients being seen in developing areas may require a modified approach.

History. All patients with eosinophilia should have a thorough history taken, with particular attention paid to travel history. A travel history should make note of dates, duration and location of travel, and any relevant exposures, such as arthropod bites or swimming in freshwater. Dietary habits, such as ingestion of seafood, game, or undercooked meat can also be helpful in making a diagnosis.^3,4

Causes of secondary eosinophilia include infectious diseases, drugs, autoimmune disorders, and allergic conditions.

Physical exam. In addition to a general physical examination, the following features may be helpful in determining the etiology of eosinophilia. Wheeze is characteristic of parasites in a lung migration phase (eg, strongyloidiasis and ascariasis) or asthma. Hepatomegaly can be seen with liver flukes, visceral larva migrans, or schistosomiasis. Periorbital edema can be observed with Trichinella infection. Loa loa, a type of filarial infection, produces a transient, migratory angioedema, often localized to the wrists and large joints (termed Calabar swelling). Dermatitis of varying intensity may suggest filarial infection, schistosomiasis, or atopy. Perianal dermatitis is observed with strongyloidiasis. Cutaneous larva migrans is characterized by a linear, serpiginous rash.^3,4

Laboratory investigations. Investigation will vary depending on the patient’s history, exposures, exam findings, and degree of eosinophilia. Any patient who is unwell or has significant eosinophilia (≥3 x 10⁹/L) may warrant more urgent referral to infectious disease, travel medicine, or hematology. Basic laboratory investigations should include a CBC with differential, routine serum chemistries, and liver enzymes. In the setting of significant eosinophilia, an electrocardiogram, cardiac enzyme levels, and a chest x-ray should be obtained to screen for end-organ damage related to eosinophilia.^3-5

In patients in whom you suspect hematologic malignancy, bone marrow aspiration and biopsy are often needed to make the diagnosis.⁵

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia.

Parasitic infections are most often diagnosed on stool examination for ova and parasites or by serology. Stool should be collected on 3 separate days to increase diagnostic yield. Certain species of Schistosoma can also be diagnosed on direct microscopy of urine specimens. Serologic assays are available for schistosomiasis, strongyloidiasis, Toxocara, fascioliasis, filariasis, and Trichinella. Further investigations for filiariasis, including blood films, eye exam, and skin snips will vary with filarial species, so expert consultation should be considered.^3,4

Our patients. The first patient with strongyloidiasis was treated with ivermectin 200 µg/kg/day orally for 2 days and experienced symptomatic improvement and resolution of eosinophilia. The second patient with ALL was admitted and referred to hematology and received induction chemotherapy. Treatment was well tolerated and the patient was discharged one week later, with appropriate follow-up.

THE TAKEAWAY

Eosinophilia is commonly encountered in primary care. The approach to eosinophilia and the differential diagnosis can be challenging. The correct diagnosis was reached in both cases by maintaining a broad differential diagnosis. Obtaining a travel and exposure history is fundamental, although noninfectious causes, including allergy, malignancy, and drug reaction, must always be considered.

CASE 1

A 13-month-old boy who was recently adopted from Ethiopia presented to a primary care physician with a 3-week history of bloody diarrhea accompanied by flatulence and bloating. Stool cultures were positive for Campylobacter and Shigella. He was prescribed azithromycin but saw only moderate improvement. He was then referred to the Infectious Diseases Department. Neonatal, pregnancy, and immunization histories were unknown and a review of systems was unremarkable. On exam, the child looked well; he weighed 9.6 kg (15th percentile), was 69.5 cm long (<3rd percentile), and his head circumference was 45 cm (10th percentile). Head and neck, cardiorespiratory, and abdominal examinations were unremarkable.

A complete blood count (CBC) showed an elevated white blood cell (WBC) count of 26 x 10⁹/L (normal: 4-10 x 10⁹/L) with predominant eosinophilia (10.4 x 10⁹/L or 40.1% of WBCs; normal: <0.45 x 10⁹/L or 0%-8%). Hemoglobin and platelets were within normal limits. Stool testing for ova and parasites showed Strongyloides stercoralis larvae. Strongyloides serology was negative and Filaria serology was equivocal.

CASE 2

A 15-year-old boy was assessed for a 3-week history of fever and eosinophilia. He had enlarged cervical lymph nodes, a new rash, and had lost 4 pounds. He denied gastrointestinal symptoms, dyspnea, headaches, or chest pain. His past medical and family histories were unremarkable and he reported no drug use or allergies. He had traveled to Cuba with his family for 15 days 3 months prior to presentation. He recalled diarrhea while traveling, which resolved spontaneously. He and his family had traveled “off the beaten track,” eating foods prepared at local establishments and swimming in local rivers. He received pre-travel immunizations.

On examination, he appeared unwell, though his vital signs were normal. He had diffuse lymphadenopathy and a petechial rash on his chest, back, upper buttocks, legs, and feet. Cardiorespiratory and abdominal examinations were unremarkable. A CBC revealed an elevated WBC count of 76.9 x 10⁹/L with predominant eosinophilia (71.5 x 10⁹/L or 92% of WBCs). Hemoglobin, platelets, electrolytes, and liver function tests were normal. The patient was referred to a tertiary care center and was admitted to the hospital. Stool testing for ova and parasites, as well as serology for parasitic infections, was negative. A bone marrow aspiration and biopsy were performed and revealed the diagnosis of acute lymphoblastic leukemia (ALL).

These 2 cases highlight how the presentation of eosinophilia can vary and how important it is to maintain a broad differential diagnosis (TABLE 1^1-4). Causes of eosinophilia are numerous and can be divided into 3 categories: primary, secondary, and idiopathic.^1,5 Hematologic malignancy, where eosinophilia is clonal, is an example of a primary etiology. Causes of secondary eosinophilia include infectious diseases, drugs (TABLE 2⁵), autoimmune disorders, and allergic conditions. Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage. Dermatologic, pulmonary, gastro­intestinal, and cardiac involvement is most common.²

Eosinophilia associated with parasitic infection

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia, with eosinophilia occurring during tissue migration or penetration.^1,3

Schistosomiasis is a chronic parasitic infection of the human vascular system. It is transmitted by contact with contaminated fresh water, where cercariae penetrate the skin. High prevalence areas include Africa and Southeast Asia. Acute infection can result in Katayama fever—a febrile illness with prominent eosinophilia that occurs 4 to 7 weeks after exposure.⁴ Diagnosis is primarily clinical with appropriate epidemiology, as serology may be negative early in infection. Praziquantel is the treatment of choice, though dosing varies by species, so expert consultation should be considered.

Soil-transmitted helminths, such as Ascaris (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancyclostoma duodenale and Necator americanus), can also cause eosinophilia during larval tissue migration. Following infection by ingestion or skin penetration, an acute respiratory illness, termed Löffler’s syndrome, can develop with associated eosinophilia.¹ Once the helminths reach the adult stage, eosinophilia subsides. Patients are most commonly treated with albendazole 400 mg orally for 3 days.⁴

Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage.Fascioliasis is common in sheep-rearing areas. Humans are infected through ingestion of aquatic plants (eg, watercress). Parasitic migration through the duodenal wall and liver parenchyma can lead to fever, right upper quadrant pain, and eosinophilia. The incubation period is 6 to 12 weeks. Diagnosis during acute infection is by serology.⁴

Filarial infections, eg lymphatic filariasis, loiasis, and onchocerciasis, can also cause eosinophilia. The rise in eosinophils can be triggered by either the adult worms or circulating microfilariae.⁴ Treatment of fascioliasis and filarial infections varies and expert consultation is recommended.

Eosinophilia associated with primary hematologic malignancy

Eosinophilia is a rare presentation of hematologic malignancy. Acute myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, and myeloproliferative disorders have all been associated with eosinophilia. Hepatosplenomegaly, generalized lymphadenopathy, and cytopenias in other cell lines are often noted. Also, the degree of eosinophilia is often more pronounced (>5 x 10⁹/L). Patients with suspected hematologic malignancy should be urgently referred for expert consultation.⁵

Consider the following approach in the assessment of patients with eosinophilia seen in the ambulatory care setting. Inpatients or patients being seen in developing areas may require a modified approach.

History. All patients with eosinophilia should have a thorough history taken, with particular attention paid to travel history. A travel history should make note of dates, duration and location of travel, and any relevant exposures, such as arthropod bites or swimming in freshwater. Dietary habits, such as ingestion of seafood, game, or undercooked meat can also be helpful in making a diagnosis.^3,4

Causes of secondary eosinophilia include infectious diseases, drugs, autoimmune disorders, and allergic conditions.

Physical exam. In addition to a general physical examination, the following features may be helpful in determining the etiology of eosinophilia. Wheeze is characteristic of parasites in a lung migration phase (eg, strongyloidiasis and ascariasis) or asthma. Hepatomegaly can be seen with liver flukes, visceral larva migrans, or schistosomiasis. Periorbital edema can be observed with Trichinella infection. Loa loa, a type of filarial infection, produces a transient, migratory angioedema, often localized to the wrists and large joints (termed Calabar swelling). Dermatitis of varying intensity may suggest filarial infection, schistosomiasis, or atopy. Perianal dermatitis is observed with strongyloidiasis. Cutaneous larva migrans is characterized by a linear, serpiginous rash.^3,4

Laboratory investigations. Investigation will vary depending on the patient’s history, exposures, exam findings, and degree of eosinophilia. Any patient who is unwell or has significant eosinophilia (≥3 x 10⁹/L) may warrant more urgent referral to infectious disease, travel medicine, or hematology. Basic laboratory investigations should include a CBC with differential, routine serum chemistries, and liver enzymes. In the setting of significant eosinophilia, an electrocardiogram, cardiac enzyme levels, and a chest x-ray should be obtained to screen for end-organ damage related to eosinophilia.^3-5

In patients in whom you suspect hematologic malignancy, bone marrow aspiration and biopsy are often needed to make the diagnosis.⁵

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia.

Parasitic infections are most often diagnosed on stool examination for ova and parasites or by serology. Stool should be collected on 3 separate days to increase diagnostic yield. Certain species of Schistosoma can also be diagnosed on direct microscopy of urine specimens. Serologic assays are available for schistosomiasis, strongyloidiasis, Toxocara, fascioliasis, filariasis, and Trichinella. Further investigations for filiariasis, including blood films, eye exam, and skin snips will vary with filarial species, so expert consultation should be considered.^3,4

Our patients. The first patient with strongyloidiasis was treated with ivermectin 200 µg/kg/day orally for 2 days and experienced symptomatic improvement and resolution of eosinophilia. The second patient with ALL was admitted and referred to hematology and received induction chemotherapy. Treatment was well tolerated and the patient was discharged one week later, with appropriate follow-up.

THE TAKEAWAY

Eosinophilia is commonly encountered in primary care. The approach to eosinophilia and the differential diagnosis can be challenging. The correct diagnosis was reached in both cases by maintaining a broad differential diagnosis. Obtaining a travel and exposure history is fundamental, although noninfectious causes, including allergy, malignancy, and drug reaction, must always be considered.

CASE 1

A 13-month-old boy who was recently adopted from Ethiopia presented to a primary care physician with a 3-week history of bloody diarrhea accompanied by flatulence and bloating. Stool cultures were positive for Campylobacter and Shigella. He was prescribed azithromycin but saw only moderate improvement. He was then referred to the Infectious Diseases Department. Neonatal, pregnancy, and immunization histories were unknown and a review of systems was unremarkable. On exam, the child looked well; he weighed 9.6 kg (15th percentile), was 69.5 cm long (<3rd percentile), and his head circumference was 45 cm (10th percentile). Head and neck, cardiorespiratory, and abdominal examinations were unremarkable.

A complete blood count (CBC) showed an elevated white blood cell (WBC) count of 26 x 10⁹/L (normal: 4-10 x 10⁹/L) with predominant eosinophilia (10.4 x 10⁹/L or 40.1% of WBCs; normal: <0.45 x 10⁹/L or 0%-8%). Hemoglobin and platelets were within normal limits. Stool testing for ova and parasites showed Strongyloides stercoralis larvae. Strongyloides serology was negative and Filaria serology was equivocal.

CASE 2

A 15-year-old boy was assessed for a 3-week history of fever and eosinophilia. He had enlarged cervical lymph nodes, a new rash, and had lost 4 pounds. He denied gastrointestinal symptoms, dyspnea, headaches, or chest pain. His past medical and family histories were unremarkable and he reported no drug use or allergies. He had traveled to Cuba with his family for 15 days 3 months prior to presentation. He recalled diarrhea while traveling, which resolved spontaneously. He and his family had traveled “off the beaten track,” eating foods prepared at local establishments and swimming in local rivers. He received pre-travel immunizations.

On examination, he appeared unwell, though his vital signs were normal. He had diffuse lymphadenopathy and a petechial rash on his chest, back, upper buttocks, legs, and feet. Cardiorespiratory and abdominal examinations were unremarkable. A CBC revealed an elevated WBC count of 76.9 x 10⁹/L with predominant eosinophilia (71.5 x 10⁹/L or 92% of WBCs). Hemoglobin, platelets, electrolytes, and liver function tests were normal. The patient was referred to a tertiary care center and was admitted to the hospital. Stool testing for ova and parasites, as well as serology for parasitic infections, was negative. A bone marrow aspiration and biopsy were performed and revealed the diagnosis of acute lymphoblastic leukemia (ALL).

These 2 cases highlight how the presentation of eosinophilia can vary and how important it is to maintain a broad differential diagnosis (TABLE 1^1-4). Causes of eosinophilia are numerous and can be divided into 3 categories: primary, secondary, and idiopathic.^1,5 Hematologic malignancy, where eosinophilia is clonal, is an example of a primary etiology. Causes of secondary eosinophilia include infectious diseases, drugs (TABLE 2⁵), autoimmune disorders, and allergic conditions. Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage. Dermatologic, pulmonary, gastro­intestinal, and cardiac involvement is most common.²

Eosinophilia associated with parasitic infection

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia, with eosinophilia occurring during tissue migration or penetration.^1,3

Schistosomiasis is a chronic parasitic infection of the human vascular system. It is transmitted by contact with contaminated fresh water, where cercariae penetrate the skin. High prevalence areas include Africa and Southeast Asia. Acute infection can result in Katayama fever—a febrile illness with prominent eosinophilia that occurs 4 to 7 weeks after exposure.⁴ Diagnosis is primarily clinical with appropriate epidemiology, as serology may be negative early in infection. Praziquantel is the treatment of choice, though dosing varies by species, so expert consultation should be considered.

Soil-transmitted helminths, such as Ascaris (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancyclostoma duodenale and Necator americanus), can also cause eosinophilia during larval tissue migration. Following infection by ingestion or skin penetration, an acute respiratory illness, termed Löffler’s syndrome, can develop with associated eosinophilia.¹ Once the helminths reach the adult stage, eosinophilia subsides. Patients are most commonly treated with albendazole 400 mg orally for 3 days.⁴

Prolonged eosinophilia that is >3 x 10⁹/L is associated with end-organ damage.Fascioliasis is common in sheep-rearing areas. Humans are infected through ingestion of aquatic plants (eg, watercress). Parasitic migration through the duodenal wall and liver parenchyma can lead to fever, right upper quadrant pain, and eosinophilia. The incubation period is 6 to 12 weeks. Diagnosis during acute infection is by serology.⁴

Filarial infections, eg lymphatic filariasis, loiasis, and onchocerciasis, can also cause eosinophilia. The rise in eosinophils can be triggered by either the adult worms or circulating microfilariae.⁴ Treatment of fascioliasis and filarial infections varies and expert consultation is recommended.

Eosinophilia associated with primary hematologic malignancy

Eosinophilia is a rare presentation of hematologic malignancy. Acute myeloid leukemia, acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, and myeloproliferative disorders have all been associated with eosinophilia. Hepatosplenomegaly, generalized lymphadenopathy, and cytopenias in other cell lines are often noted. Also, the degree of eosinophilia is often more pronounced (>5 x 10⁹/L). Patients with suspected hematologic malignancy should be urgently referred for expert consultation.⁵

Consider the following approach in the assessment of patients with eosinophilia seen in the ambulatory care setting. Inpatients or patients being seen in developing areas may require a modified approach.

History. All patients with eosinophilia should have a thorough history taken, with particular attention paid to travel history. A travel history should make note of dates, duration and location of travel, and any relevant exposures, such as arthropod bites or swimming in freshwater. Dietary habits, such as ingestion of seafood, game, or undercooked meat can also be helpful in making a diagnosis.^3,4

Causes of secondary eosinophilia include infectious diseases, drugs, autoimmune disorders, and allergic conditions.

Physical exam. In addition to a general physical examination, the following features may be helpful in determining the etiology of eosinophilia. Wheeze is characteristic of parasites in a lung migration phase (eg, strongyloidiasis and ascariasis) or asthma. Hepatomegaly can be seen with liver flukes, visceral larva migrans, or schistosomiasis. Periorbital edema can be observed with Trichinella infection. Loa loa, a type of filarial infection, produces a transient, migratory angioedema, often localized to the wrists and large joints (termed Calabar swelling). Dermatitis of varying intensity may suggest filarial infection, schistosomiasis, or atopy. Perianal dermatitis is observed with strongyloidiasis. Cutaneous larva migrans is characterized by a linear, serpiginous rash.^3,4

Laboratory investigations. Investigation will vary depending on the patient’s history, exposures, exam findings, and degree of eosinophilia. Any patient who is unwell or has significant eosinophilia (≥3 x 10⁹/L) may warrant more urgent referral to infectious disease, travel medicine, or hematology. Basic laboratory investigations should include a CBC with differential, routine serum chemistries, and liver enzymes. In the setting of significant eosinophilia, an electrocardiogram, cardiac enzyme levels, and a chest x-ray should be obtained to screen for end-organ damage related to eosinophilia.^3-5

In patients in whom you suspect hematologic malignancy, bone marrow aspiration and biopsy are often needed to make the diagnosis.⁵

In returning travelers and international adoptees, multicellular helminthic parasites are the most common causes of eosinophilia.

Parasitic infections are most often diagnosed on stool examination for ova and parasites or by serology. Stool should be collected on 3 separate days to increase diagnostic yield. Certain species of Schistosoma can also be diagnosed on direct microscopy of urine specimens. Serologic assays are available for schistosomiasis, strongyloidiasis, Toxocara, fascioliasis, filariasis, and Trichinella. Further investigations for filiariasis, including blood films, eye exam, and skin snips will vary with filarial species, so expert consultation should be considered.^3,4

Our patients. The first patient with strongyloidiasis was treated with ivermectin 200 µg/kg/day orally for 2 days and experienced symptomatic improvement and resolution of eosinophilia. The second patient with ALL was admitted and referred to hematology and received induction chemotherapy. Treatment was well tolerated and the patient was discharged one week later, with appropriate follow-up.

THE TAKEAWAY

Eosinophilia is commonly encountered in primary care. The approach to eosinophilia and the differential diagnosis can be challenging. The correct diagnosis was reached in both cases by maintaining a broad differential diagnosis. Obtaining a travel and exposure history is fundamental, although noninfectious causes, including allergy, malignancy, and drug reaction, must always be considered.

ILLUSTRATIVE CASE

A 64-year-old woman presents to your office for a follow-up visit for her hypertension. She is currently managed on lisinopril 20 mg/d and hydrochlorothiazide 25 mg/d without any problems. The patient’s blood pressure (BP) in the office today is 148/84 mm Hg, but her home blood pressure (HBP) readings are much lower (see TABLE). Should you increase her lisinopril dose today?

Hypertension has been diagnosed on the basis of office readings of BP for almost a century, but the readings can be so inaccurate that they are not useful.² The US Preventive Services Task Force recommends the use of ambulatory blood pressure monitoring (ABPM) to accurately diagnose hypertension in all patients, while The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends ABPM for patients suspected of having white-coat hypertension and any patient with resistant hypertension,^3,4 but ABPM is not always acceptable to patients.⁵

Guidelines recommend HBP monitoring for long-term follow-up of hypertension

The European Society of Hypertension practice guideline on HBP monitoring suggests that HBP values <130/80 mm Hg may be considered normal, while a mean HBP ≥135/85 mm Hg is considered elevated.⁹ The guideline recommends HBP monitoring for 3 to 7 days prior to a patient’s follow-up appointment with 2 readings taken one to 2 minutes apart in the morning and evening.⁹ In a busy clinic, averaging all of these home values can be time-consuming.

So how can primary care physicians accurately and efficiently streamline the process? This study sought to answer that question.

STUDY SUMMARY

When 3 of 10 readings are elevated, it’s predictive

This multicenter trial compared HBP monitoring to 24-hour ABPM in 286 patients with uncomplicated essential hypertension to determine the optimal percentage of HBP readings needed to diagnose uncontrolled BP (HBP ≥135/85 mm Hg). Patients were included if they were diagnosed with uncomplicated hypertension, not pregnant, ≥18 years of age, and taking ≤3 antihypertensive medications. Medication compliance was verified by a study nurse at a clinic visit. Patients were excluded if they had a significant abnormal left ventricular mass index (women >59 g/m²; men >64 g/m²), coronary artery or renal disease, secondary hypertension, serum creatinine exceeding 1.6 mg/dL, aortic valve stenosis, upper limb obstructive atherosclerosis, or BP >180/100 mm Hg.

The researchers found that if at least 3 of the last 10 home BP readings were elevated, the patient was likely to have hypertension on 24-hour ambulatory monitoring.

Approximately half of the participants were women (53%), average body mass index was 29.4 kg/m², and the average number of hypertension medications being taken was 2.4. The patients were instructed to take 2 BP readings (one minute apart) at home 3 times daily, in the morning (between 6 am and 10 am), at noon, and in the evening (between 6 pm and 10 pm), and to record only the second reading for 7 days. Only the morning and evening readings were used for analysis in the study. The 24-hour ABP was measured every 30 minutes during the daytime hours and every 60 minutes overnight. The primary outcome was to determine the optimal number of systolic HBP readings above goal (135 mm Hg), from the last 10 recordings, that would best predict elevated 24-hour ABP. Secondary outcomes were various cardiovascular markers of target end-organ damage.

The researchers found that if at least 3 of the last 10 HBP readings were elevated (≥135 mm Hg systolic), the patient was likely to have hypertension on 24-hour ABPM (≥130 mm Hg). When patients had <3 HBP elevations out of 10 readings, their mean (±standard deviation [SD]) 24-hour ambulatory daytime systolic BP was 132.7 (±11.1) mm Hg and their mean systolic HBP value was 120.4 (±9.8) mm Hg. When patients had ≥3 HBP elevations, their mean 24-hour ambulatory daytime systolic BP was 143.4 (±11.2) mm Hg and their mean systolic HBP value was 147.4 (±10.5) mm Hg.

The positive and negative predictive values of ≥3 HBP elevations were 0.85 (95% confidence interval [CI], 0.78-0.91) and 0.56 (95% CI, 0.48-0.64), respectively, for a 24-hour systolic ABP of ≥130 mm Hg. Three elevations or more in HBP, out of the last 10 readings, was also an indicator for target organ disease assessed by aortic stiffness and increased left ventricular mass and decreased function.

The sensitivity and specificity of ≥3 elevations for mean 24-hour ABP systolic readings ≥130 mm Hg were 62% and 80%, respectively, and for 24-hour ABP daytime systolic readings ≥135 mm Hg were 65% and 77%, respectively.

WHAT’S NEW

Monitoring home BP can be simplified

The researchers found that HBP monitoring correlates well with ABPM and that their method provides clinicians with a simple way (3 of the past 10 measurements ≥135 mm Hg systolic) to use HBP readings to make clinical decisions regarding BP management.

CAVEATS

Ideal BP goals are hazy, and a lot of patient education is required

Conflicting information and opinions remain regarding the ideal intensive and standard BP goals in different populations.^10,11 Systolic BP goals in this study (≥130 mm Hg for overall 24-hour ABP and ≥135 mm Hg for 24-hour ABP daytime readings) are recommended by some experts, but are not commonly recognized goals in the United States. This study found good correlation between HBP and ABPM at these goals, and it seems likely that this correlation could be extrapolated for similar BP goals.

Patients using home blood pressure monitors should be counseled on how to determine the appropriate cuff size so that measurements are accurate.

Other limitations are that: 1) The study focused only on systolic BP goals; 2) Patients in the study adhered to precise instructions on BP monitoring. HBP monitoring requires significant patient education on the proper use of the equipment and the monitoring schedule; and 3) While end-organ complication outcomes showed numerical decreases in function, the clinical significance of these reductions for patients is unclear.

CHALLENGES TO IMPLEMENTATION

Cost of device and improper cuff sizes could be barriers

The cost of HBP monitors ($40-$60) has decreased significantly over time, but the devices are not always covered by insurance and may be unobtainable for some people. Additionally, patients should be counseled on how to determine the appropriate cuff size to ensure the accuracy of the measurements.

The British Hypertensive Society maintains a list of validated BP devices on their Web site: http://bhsoc.org/bp-monitors/bp-monitors.¹²

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old woman presents to your office for a follow-up visit for her hypertension. She is currently managed on lisinopril 20 mg/d and hydrochlorothiazide 25 mg/d without any problems. The patient’s blood pressure (BP) in the office today is 148/84 mm Hg, but her home blood pressure (HBP) readings are much lower (see TABLE). Should you increase her lisinopril dose today?

Hypertension has been diagnosed on the basis of office readings of BP for almost a century, but the readings can be so inaccurate that they are not useful.² The US Preventive Services Task Force recommends the use of ambulatory blood pressure monitoring (ABPM) to accurately diagnose hypertension in all patients, while The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends ABPM for patients suspected of having white-coat hypertension and any patient with resistant hypertension,^3,4 but ABPM is not always acceptable to patients.⁵

Guidelines recommend HBP monitoring for long-term follow-up of hypertension

The European Society of Hypertension practice guideline on HBP monitoring suggests that HBP values <130/80 mm Hg may be considered normal, while a mean HBP ≥135/85 mm Hg is considered elevated.⁹ The guideline recommends HBP monitoring for 3 to 7 days prior to a patient’s follow-up appointment with 2 readings taken one to 2 minutes apart in the morning and evening.⁹ In a busy clinic, averaging all of these home values can be time-consuming.

So how can primary care physicians accurately and efficiently streamline the process? This study sought to answer that question.

STUDY SUMMARY

When 3 of 10 readings are elevated, it’s predictive

This multicenter trial compared HBP monitoring to 24-hour ABPM in 286 patients with uncomplicated essential hypertension to determine the optimal percentage of HBP readings needed to diagnose uncontrolled BP (HBP ≥135/85 mm Hg). Patients were included if they were diagnosed with uncomplicated hypertension, not pregnant, ≥18 years of age, and taking ≤3 antihypertensive medications. Medication compliance was verified by a study nurse at a clinic visit. Patients were excluded if they had a significant abnormal left ventricular mass index (women >59 g/m²; men >64 g/m²), coronary artery or renal disease, secondary hypertension, serum creatinine exceeding 1.6 mg/dL, aortic valve stenosis, upper limb obstructive atherosclerosis, or BP >180/100 mm Hg.

The researchers found that if at least 3 of the last 10 home BP readings were elevated, the patient was likely to have hypertension on 24-hour ambulatory monitoring.

Approximately half of the participants were women (53%), average body mass index was 29.4 kg/m², and the average number of hypertension medications being taken was 2.4. The patients were instructed to take 2 BP readings (one minute apart) at home 3 times daily, in the morning (between 6 am and 10 am), at noon, and in the evening (between 6 pm and 10 pm), and to record only the second reading for 7 days. Only the morning and evening readings were used for analysis in the study. The 24-hour ABP was measured every 30 minutes during the daytime hours and every 60 minutes overnight. The primary outcome was to determine the optimal number of systolic HBP readings above goal (135 mm Hg), from the last 10 recordings, that would best predict elevated 24-hour ABP. Secondary outcomes were various cardiovascular markers of target end-organ damage.

The researchers found that if at least 3 of the last 10 HBP readings were elevated (≥135 mm Hg systolic), the patient was likely to have hypertension on 24-hour ABPM (≥130 mm Hg). When patients had <3 HBP elevations out of 10 readings, their mean (±standard deviation [SD]) 24-hour ambulatory daytime systolic BP was 132.7 (±11.1) mm Hg and their mean systolic HBP value was 120.4 (±9.8) mm Hg. When patients had ≥3 HBP elevations, their mean 24-hour ambulatory daytime systolic BP was 143.4 (±11.2) mm Hg and their mean systolic HBP value was 147.4 (±10.5) mm Hg.

The positive and negative predictive values of ≥3 HBP elevations were 0.85 (95% confidence interval [CI], 0.78-0.91) and 0.56 (95% CI, 0.48-0.64), respectively, for a 24-hour systolic ABP of ≥130 mm Hg. Three elevations or more in HBP, out of the last 10 readings, was also an indicator for target organ disease assessed by aortic stiffness and increased left ventricular mass and decreased function.

The sensitivity and specificity of ≥3 elevations for mean 24-hour ABP systolic readings ≥130 mm Hg were 62% and 80%, respectively, and for 24-hour ABP daytime systolic readings ≥135 mm Hg were 65% and 77%, respectively.

WHAT’S NEW

Monitoring home BP can be simplified

The researchers found that HBP monitoring correlates well with ABPM and that their method provides clinicians with a simple way (3 of the past 10 measurements ≥135 mm Hg systolic) to use HBP readings to make clinical decisions regarding BP management.

CAVEATS

Ideal BP goals are hazy, and a lot of patient education is required

Conflicting information and opinions remain regarding the ideal intensive and standard BP goals in different populations.^10,11 Systolic BP goals in this study (≥130 mm Hg for overall 24-hour ABP and ≥135 mm Hg for 24-hour ABP daytime readings) are recommended by some experts, but are not commonly recognized goals in the United States. This study found good correlation between HBP and ABPM at these goals, and it seems likely that this correlation could be extrapolated for similar BP goals.

Patients using home blood pressure monitors should be counseled on how to determine the appropriate cuff size so that measurements are accurate.

Other limitations are that: 1) The study focused only on systolic BP goals; 2) Patients in the study adhered to precise instructions on BP monitoring. HBP monitoring requires significant patient education on the proper use of the equipment and the monitoring schedule; and 3) While end-organ complication outcomes showed numerical decreases in function, the clinical significance of these reductions for patients is unclear.

CHALLENGES TO IMPLEMENTATION

Cost of device and improper cuff sizes could be barriers

The cost of HBP monitors ($40-$60) has decreased significantly over time, but the devices are not always covered by insurance and may be unobtainable for some people. Additionally, patients should be counseled on how to determine the appropriate cuff size to ensure the accuracy of the measurements.

The British Hypertensive Society maintains a list of validated BP devices on their Web site: http://bhsoc.org/bp-monitors/bp-monitors.¹²

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old woman presents to your office for a follow-up visit for her hypertension. She is currently managed on lisinopril 20 mg/d and hydrochlorothiazide 25 mg/d without any problems. The patient’s blood pressure (BP) in the office today is 148/84 mm Hg, but her home blood pressure (HBP) readings are much lower (see TABLE). Should you increase her lisinopril dose today?

Hypertension has been diagnosed on the basis of office readings of BP for almost a century, but the readings can be so inaccurate that they are not useful.² The US Preventive Services Task Force recommends the use of ambulatory blood pressure monitoring (ABPM) to accurately diagnose hypertension in all patients, while The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends ABPM for patients suspected of having white-coat hypertension and any patient with resistant hypertension,^3,4 but ABPM is not always acceptable to patients.⁵

Guidelines recommend HBP monitoring for long-term follow-up of hypertension

The European Society of Hypertension practice guideline on HBP monitoring suggests that HBP values <130/80 mm Hg may be considered normal, while a mean HBP ≥135/85 mm Hg is considered elevated.⁹ The guideline recommends HBP monitoring for 3 to 7 days prior to a patient’s follow-up appointment with 2 readings taken one to 2 minutes apart in the morning and evening.⁹ In a busy clinic, averaging all of these home values can be time-consuming.

So how can primary care physicians accurately and efficiently streamline the process? This study sought to answer that question.

STUDY SUMMARY

When 3 of 10 readings are elevated, it’s predictive

This multicenter trial compared HBP monitoring to 24-hour ABPM in 286 patients with uncomplicated essential hypertension to determine the optimal percentage of HBP readings needed to diagnose uncontrolled BP (HBP ≥135/85 mm Hg). Patients were included if they were diagnosed with uncomplicated hypertension, not pregnant, ≥18 years of age, and taking ≤3 antihypertensive medications. Medication compliance was verified by a study nurse at a clinic visit. Patients were excluded if they had a significant abnormal left ventricular mass index (women >59 g/m²; men >64 g/m²), coronary artery or renal disease, secondary hypertension, serum creatinine exceeding 1.6 mg/dL, aortic valve stenosis, upper limb obstructive atherosclerosis, or BP >180/100 mm Hg.

The researchers found that if at least 3 of the last 10 home BP readings were elevated, the patient was likely to have hypertension on 24-hour ambulatory monitoring.

Approximately half of the participants were women (53%), average body mass index was 29.4 kg/m², and the average number of hypertension medications being taken was 2.4. The patients were instructed to take 2 BP readings (one minute apart) at home 3 times daily, in the morning (between 6 am and 10 am), at noon, and in the evening (between 6 pm and 10 pm), and to record only the second reading for 7 days. Only the morning and evening readings were used for analysis in the study. The 24-hour ABP was measured every 30 minutes during the daytime hours and every 60 minutes overnight. The primary outcome was to determine the optimal number of systolic HBP readings above goal (135 mm Hg), from the last 10 recordings, that would best predict elevated 24-hour ABP. Secondary outcomes were various cardiovascular markers of target end-organ damage.

The researchers found that if at least 3 of the last 10 HBP readings were elevated (≥135 mm Hg systolic), the patient was likely to have hypertension on 24-hour ABPM (≥130 mm Hg). When patients had <3 HBP elevations out of 10 readings, their mean (±standard deviation [SD]) 24-hour ambulatory daytime systolic BP was 132.7 (±11.1) mm Hg and their mean systolic HBP value was 120.4 (±9.8) mm Hg. When patients had ≥3 HBP elevations, their mean 24-hour ambulatory daytime systolic BP was 143.4 (±11.2) mm Hg and their mean systolic HBP value was 147.4 (±10.5) mm Hg.

The positive and negative predictive values of ≥3 HBP elevations were 0.85 (95% confidence interval [CI], 0.78-0.91) and 0.56 (95% CI, 0.48-0.64), respectively, for a 24-hour systolic ABP of ≥130 mm Hg. Three elevations or more in HBP, out of the last 10 readings, was also an indicator for target organ disease assessed by aortic stiffness and increased left ventricular mass and decreased function.

The sensitivity and specificity of ≥3 elevations for mean 24-hour ABP systolic readings ≥130 mm Hg were 62% and 80%, respectively, and for 24-hour ABP daytime systolic readings ≥135 mm Hg were 65% and 77%, respectively.

WHAT’S NEW

Monitoring home BP can be simplified

The researchers found that HBP monitoring correlates well with ABPM and that their method provides clinicians with a simple way (3 of the past 10 measurements ≥135 mm Hg systolic) to use HBP readings to make clinical decisions regarding BP management.

CAVEATS

Ideal BP goals are hazy, and a lot of patient education is required

Conflicting information and opinions remain regarding the ideal intensive and standard BP goals in different populations.^10,11 Systolic BP goals in this study (≥130 mm Hg for overall 24-hour ABP and ≥135 mm Hg for 24-hour ABP daytime readings) are recommended by some experts, but are not commonly recognized goals in the United States. This study found good correlation between HBP and ABPM at these goals, and it seems likely that this correlation could be extrapolated for similar BP goals.

Patients using home blood pressure monitors should be counseled on how to determine the appropriate cuff size so that measurements are accurate.

Other limitations are that: 1) The study focused only on systolic BP goals; 2) Patients in the study adhered to precise instructions on BP monitoring. HBP monitoring requires significant patient education on the proper use of the equipment and the monitoring schedule; and 3) While end-organ complication outcomes showed numerical decreases in function, the clinical significance of these reductions for patients is unclear.

CHALLENGES TO IMPLEMENTATION

Cost of device and improper cuff sizes could be barriers

The cost of HBP monitors ($40-$60) has decreased significantly over time, but the devices are not always covered by insurance and may be unobtainable for some people. Additionally, patients should be counseled on how to determine the appropriate cuff size to ensure the accuracy of the measurements.

The British Hypertensive Society maintains a list of validated BP devices on their Web site: http://bhsoc.org/bp-monitors/bp-monitors.¹²

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Most family physicians are accustomed to treating active patients with shin splints and stress fractures. But many are less familiar with, and slower to recognize, other sources of exertional leg pain (ELP), defined as exercise-related pain that localizes in the lower extremity distal to the knee and proximal to the talocrural joint.¹

ELP has a broad differential diagnosis that includes other musculoskeletal conditions—most notably chronic exertional compartment syndrome (CECS), which has been found to affect 33% of athletes with chronic ELP¹—as well as a number of vascular and neurologic causes.^2-4 In addition, etiologies may overlap. Greater awareness of the many causes of ELP can help you to avoid the unnecessary use of expensive diagnostic tests as well as delayed diagnosis and treatment.

A thorough medical and activity history, symptom review, and physical examination are your most important tools when patients present with ELP. When the cause is not obvious or the patient fails to respond to conservative measures, x-rays, magnetic resonance imaging (MRI), vascular studies, electromyography and nerve conduction studies, and/or intracompartmental pressure testing may be needed to find the source of the symptoms. In the text that follows, we review both common and relatively uncommon sources of ELP, using a stepwise diagnostic approach. You’ll find a diagnostic challenge, in which you can test your skills and a more comprehensive differential diagnosis in the TABLE.^1-3,5-9

Musculoskeletal injuries: Shin splints and beyond

Medial tibial stress syndrome (MTSS), commonly known as shin splints, is characterized by pain and tenderness over the posteromedial aspect of the distal tibia.³ It typically results in diffuse pain that occurs with exercise, but may persist at rest in severe cases.^3-6 Less often, localized swelling may also be present.²

MTSS accounts for between 6% and 16% of all running injuries.^2,10 It is associated with a spectrum of tibial stress injuries, including periostitis, tendinopathy, and stress reaction, with dysfunction of the tibialis posterior, tibialis anterior, and soleus muscles thought to be contributing factors.^2,11 Intrinsic factors include high body mass index (BMI), female sex, excessive internal and external hip rotation, hyperpronation, and hyper plantar flexion.^2,10,12

X-rays of the leg are typically normal in patients with MTSS and should be considered only if the clinical presentation suggests the possibility of an alternative diagnosis, such as a stress fracture or tumor.^2-4,13 Advanced imaging such as MRI or triple phase bone scans (TPBS) are useful when the diagnosis is in question and will reveal an abnormally high signal along the posterior medial tibial surface or the classic train-track appearance of nucleotide uptake in patients with MTSS.² MRI readily shows periosteal reaction and bony edema and has a sensitivity of 78% to 89% and a specificity of 33% to 100% for the diagnosis of MTSS.^14,15

While ice, NSAIDs, proper conditioning, physical therapy, and activity modification are all appropriate treatment for shin splints, none of these interventions are more effective than rest alone.

Initial management of MTSS is conservative, with the mainstay of treatment consisting of rest, ice, and nonsteroidal anti-inflammatory drugs (NSAIDs).^3,13,16 While ice, NSAIDs, proper conditioning, physical therapy to stretch and strengthen the calf musculature, rigid orthotics to correct foot hyperpronation, and activity modification are all appropriate treatments, randomized controlled trials have shown none of these interventions to be more effective than rest alone.² Non-operative treatment is usually successful, but surgery may be required for severe or refractory cases. Procedures include posteromedial fasciotomy, release of the medial soleus fascial bridge, deep compartment fasciotomy, or removal of a section of the distal tibia periosteum.^3,4

Lower extremity stress fracture. Stress fractures are caused by repetitive loading that results in microtrauma, including bony microfractures. The vast majority of cases—80% to 95% of stress fractures—affect the lower extremities, and most involve the tibia.^2-4,6,13,17 The most common presentation is an insidious onset of pain over a specific bony area with a normal appearance, although localized swelling or erythema may occasionally be present.^3,14,17,18 The pain may be reproduced or worsened by weight-bearing activities and relieved by rest.^14,18

Consider the female athlete triad. In evaluating a patient with a stress fracture, pay close attention to dietary history, BMI, and, in female athletes, take a detailed menstrual history. Such patients are at risk for amenorrhea, low bone mineral density, and nutritional deficits—the “female athlete triad,” which carries an increased risk of stress fractures.^3,14,17-19

Stress fractures can often be diagnosed with a thorough medical history and physical, with imaging used for confirmation.^6,14,17,18 Historical features of a stress fracture that may differentiate it from MTSS include pain that is unilateral and absent at rest and occurs with more prolonged activity, as well as post-exercise and/or nocturnal pain. Notable physical exam features include pain that is reproduced in a focal area with a single leg hop or percussion with a tuning fork or ultrasound.^5,11,17

Initially, sensitivity for a plain radiograph is as low as 10%.^2,11 Abnormalities on x-ray are usually seen after 2 to 8 weeks of symptoms^2,7,11 and may include a faint periosteal reaction, a fluffy area of callus, or a cortical lucency sometimes referred to as the “dreaded black line.”^3,6,17 If a radiographic exam shows evidence of a stress fracture, further imaging is typically unnecessary. MRI or TPBS is suggested, however, when x-rays appear normal but suspicion of a stress fracture remains.^3,17,18 MRI may show edema within 3 days of symptom onset and is more sensitive and specific than computed tomography (CT) or TPBS for diagnosing stress fractures of the tibia.^2,16

Treatment of tibial stress fractures is typically non-operative and consists of alterations in activity (eg, non weight-bearing), correction of nutritional deficits, such as inadequate caloric intake or too little calcium or iron, and addressing problems with footwear, training regimen, and/or running surface.^3,14,18 Fibular and posteromedial tibial stress fractures are considered low risk and heal with weight-bearing restrictions and rest, initially for a minimum of 2 to 4 weeks.³

Posteromedial tibia injuries tend to heal well because they are on the compression side of the bone. Anterior tibia stress fractures, which are located on the tension side of the bone^2,7 and account for approximately 5% of all tibia stress fractures, are more prone to non-union or progression to a complete fracture.^7,20 Thus, anterior tibia stress injuries warrant a more aggressive approach, with treatment options including non-weight bearing status that may last longer than 8 weeks, pneumatic brace casting, and/or orthopedic referral to evaluate for surgical intervention.^7,20-22 Time for radiographic evidence of healing may exceed 8 months, so early surgical intervention should be considered, especially for high-level athletes.^7,20,21

When to suspect chronic exertional compartment syndrome

Leg pain in CECS results from increased pressure within the lower extremity fascial compartments temporally related to exercise.^2,23,24 Its incidence in the general population is unknown, but CECS has been found to range from 14% to 27% in patients with previously undiagnosed leg pain^1,14,25 and to affect about a third of athletes with chronic ELP. In addition, CECS has been found in 90% of patients who have both diabetes and ELP with normal findings on vascular studies.^1,3,4,26

Pain associated with a stress fracture can typically be reproduced in a focal area with a single leg hop or percussion with a tuning fork.

The anterior compartment is most commonly affected, followed by the lateral, deep posterior, and superficial posterior compartments.^3,13,23,27 Symptoms are bilateral 60% to 95% of the time.^2,13,14,25 Factors contributing to CECS include fixed muscular compartment constraints, muscle swelling, thickened fascia, muscle hypertrophy related to resistance training, dynamic muscular contraction patterns, and low muscle capillary supply. Stretching of fascial pain receptors and pressure fibers and inadequate myocyte response to increased metabolism may play a role, as well.^14,28

The initial clinical presentation is usually predictable leg pain—ie, pain that begins at about the same time, distance, or intensity of a workout and resolves with rest; numbness and weakness may occur as the workout progresses. In time, leg pain associated with CECS may be present with everyday activity or at rest. The physical exam may be normal or reveal swelling, tenderness over the involved compartments, pain with passive digit or ankle motion, and palpable muscle herniation.¹⁴

Measurement of intracompartmental pressure before and after exercise is the gold standard for diagnosis of CECS.^2,14,27 Pre-exercise values ≥15 mm Hg and post-exercise values ≥30 mm Hg at one minute or ≥20 mm Hg at 5 minutes are all considered diagnostic of CECS,¹¹ although these widely accepted criteria for bilateral testing of all compartments yields a false-positive rate of 5%.²⁷ CECS is almost always bilateral,²⁹ and some clinicians advocate limiting the number of needle insertions by taking only post-exercise measurements and testing only symptomatic compartments in one limb.

Imaging has limited value, as both x-rays and MRIs are usually normal.¹⁴ How­ever, post-exertional T2-weighted MRI findings of muscular edema correspond to increased intracompartmental pressures, with a sensitivity of 87% and a specificity of 62%.^14,24,30,31 Infrared spectroscopy, which measures levels of oxygenated and deoxygenated blood, is sensitive for CECS when the post-exercise ratio of deoxygenated to oxygenated blood remains elevated.^14,24 Neither of these screening modalities is routinely obtained or considered diagnostic, however. Their chief role is to exclude an alternative diagnosis.¹⁴

Treatment and symptom relief. Discontinuing or modifying the aggravating activity typically brings relief of CECS. But this is not a long-term solution, as symptoms are likely to recur when the patient returns to the activity in question.¹ The definitive treatment is compartment release via fasciotomy. Success rates for anterior and lateral compartment releases are >80%.^1,28 The success of fasciotomy of posterior compartments, however, is <50%—a finding attributed to more complex anatomy, difficult visualization, and the presence of additional compartments.^1,32

When the cause is vascular

Arterial endofibrosis—the fibrotic thickening of the intima of an artery—is thought to be caused by repetitive hip flexion.⁸ This results in hyperplasia, wall thickening, and eventual stenosis of the vessel, with 90% of cases affecting the external iliac artery.^8,33 The condition is most common in activities such as cycling, but is also seen in such activities as running, skiing, soccer, and rugby. Symptoms are typically unilateral, but an estimated 15% of patients experience bilateral symptoms.^8,33

Loss of power in the affected leg, with intermittent claudication and pain due to presumed ischemia from the vascular defect, is the usual presentation, although some patients develop cramping of the buttocks and/or paresthesia of the affected leg and foot during uphill running or cycling.^8,33 The physical exam is often normal, but there may be a post-exercise arterial bruit over the femoral artery when the hip is flexed.^8,34

Consider spinal stenosis in patients who report bilateral lower extremity numbness and tingling that radiates down the legs.

Pre-exercise ankle-brachial index (ABI) <0.5 and post-exercise ABI <0.66 at one minute is suggestive of moderate arterial endofibrosis, with 90% sensitivity and 87% specificity.^8,33,34 Arterial ultrasound and color Doppler may also be used for diagnosis, but are often operator dependent. Magnetic resonance angiography (MRA), while more expensive, can detect excessive kinking or compression of the vessel and is not operator dependent.^8,33 Angioplastic balloon catheter dilation and stenting, bypass surgery, vascular reconstruction and endarterectomy with vein patch are the options for treatment. The success rates of the various interventions are unknown due to a lack of head-to-head studies and long-term follow-up.^8,33

Popliteal artery entrapment syndrome (PAES) is a constellation of symptoms caused by vascular impingement in the popliteal fossa of the knee.^8,34 The typical presenting symptoms are lower limb ischemia and pain caused by intense exercise that resolves quickly afterwards. Symptoms correlate more with the intensity than the duration of exercise.^3,8

PAES is usually caused by a variant of the gastrocnemius muscle in which a medial head passes behind the popliteal artery in males younger than 30 years.^8,33-35 Less commonly, it is the result of an overuse or acute orthopedic injury that irritates structures surrounding the popliteal fossa.^8,34 PAES affects football, basketball, and soccer players, as well as runners because of excessive dorsiflexion and plantar flexion of the ankle.^3,4

The physical exam for a patient with PAES is typically normal, but a post-exercise popliteal bruit with weak peripheral pulses may be elicited.^8,33 An ABI in the neutral, forced dorsiflexion and forced plantar flexion positions can serve as a useful screening tool. An ABI <0.9 is abnormal, with a sensitivity and specificity of 90% and 98%, respectively, for stenosis >50%.^2,36

An ankle-brachial index in the neutral, forced dorsiflexion and forced plantar flexion positions is a useful screening tool for popliteal artery entrapment syndrome.

Arteriography is the gold standard for diagnosis of PAES. Contrast arteriography is most commonly used because of its availability and cost. But MRA better differentiates functional from anatomic entrapment—a differentiation that less invasive tests, such as duplex ultrasound studies, lack the specificity to reveal.^8,34 Treatment requires either surgical removal of the offending musculotendinous structures or arterial bypass and grafting of the chronically impinged area, as conservative therapies lack efficacy.^2,8,34

Cystic adventitial disease (CAD) is the narrowing of an artery by mucoid cysts in the arterial wall or adventitia.^8,9 It is a rare condition, accounting for just 0.1% of all vascular diseases, most commonly occurring in men in their mid-40s.^8,33 CAD is thought to be the result of mucin-producing cells being haphazardly incorporated into the adventitia during arterial development. About 85% of patients whose popliteal artery is affected in this way will experience intermittent claudication with activity.^8,9

On exam, such patients often have diminished ankle-brachial pressure indices, and duplex ultrasound often reveals stenosis in the affected artery, as well as a collection of mucoid cysts in the adventitia.^8,9

Diagnosis can be confirmed by MRA.^8,37 Evidence for the treatment of CAD is largely anecdotal.⁹ Cysts may be aspirated but tend to recur, and stenting does not correct the cystic-induced narrowing of the vessel. Surgical removal of the cysts is the only successful treatment.^8,9

Neurologic causes to consider

Spinal stenosis is caused by central canal narrowing secondary to congenital abnormalities, trauma, or, most commonly, degenerative changes in the lumbar spine. Spinal stenosis is generally seen in men or women ages 50 to 70 years.³⁸ Patients experience unilateral or bilateral claudication that improves with sitting or flexion of the spine⁵ and may develop bilateral lower extremity numbness and tingling from the buttocks that radiates down the legs. Diagnosis is typically made with a combination of a lumbar x-ray and an MRI, which will show nerve compression and bony overgrowth.³⁸ CT myelogram, another imaging option, isless sensitive in the acute phase, but can be used to monitor the disease course.

Initial treatment includes physical therapy and NSAIDs.⁵ If conservative therapy fails, epidural or nerve root corticosteroid injections and surgical decompression or laminectomy are options.³⁸

Nerve entrapment is a less common source of lower extremity pain in which the superficial peroneal nerve is most often affected.^4,12,17,39 Trauma is the usual cause of nerve entrapment, but it may also be associated with overuse, most notably related to dance, soccer, or tennis.^2,14,40,41 The most likely anatomic site is where the nerve exits the deep fascia within the lateral compartment in the lower third of the leg.^39,40 Less frequently, the common peroneal nerve at the fibular neck, the saphenous nerve as it passes through Hunter’s canal, the posterior tibial nerve at the tarsal tunnel, and the sural nerve in the posterior calf may be affected.^{3,4,12,17,20,40,41} Entrapment of the peroneal nerve may be associated with activities involving repetitive inversion and eversion, such as running and cycling. Injury of the saphenous nerve is seen in sports involving repetitive knee flexion like rowing and cycling. Sural nerve entrapment is a result of crural fascia compression of the nerve during activities like running and track.^{3,14,40,42,43}

Patients typically experience burning, tingling, and radiation of pain with activity. Symptoms worsen with continued exercise. The physical exam is often normal, especially early in the disease process, but may reveal sensory loss, motor weakness, and a loss of reflexes.^2,40 Patients with superficial peroneal nerve involvement may have distal lateral leg pain that radiates into the dorsum of the foot, often exacerbated by lower leg percussion and resulting in diminished sensation.¹ Common peroneal nerve involvement may alter sensation of the lateral leg, as well, but may also cause foot drop.² The saphenous nerve can cause medial knee or leg symptoms, while the sural nerve can yield pain in the lateral ankle and foot.²

To diagnose nerve entrapment, electromyography and nerve conduction velocities at the level of the lesion may yield positive results 3 to 4 weeks after symptom onset.^2,13,40 There are wide ranges of sensitivity and specificity for these studies, but they are nonetheless considered the tests of choice for nerve entrapment.^1,44 Conservative treatment with activity modification, physical therapy, massage, and NSAIDs is often sufficient,² with surgical management warranted only for refractory cases.^2,14,40,41

CORRESPONDENCE
Jonathan A. Becker, MD, CAQSM, University of Louisville Department of Family and Geriatric Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; jon.becker@louisville@edu.

Most family physicians are accustomed to treating active patients with shin splints and stress fractures. But many are less familiar with, and slower to recognize, other sources of exertional leg pain (ELP), defined as exercise-related pain that localizes in the lower extremity distal to the knee and proximal to the talocrural joint.¹

ELP has a broad differential diagnosis that includes other musculoskeletal conditions—most notably chronic exertional compartment syndrome (CECS), which has been found to affect 33% of athletes with chronic ELP¹—as well as a number of vascular and neurologic causes.^2-4 In addition, etiologies may overlap. Greater awareness of the many causes of ELP can help you to avoid the unnecessary use of expensive diagnostic tests as well as delayed diagnosis and treatment.

A thorough medical and activity history, symptom review, and physical examination are your most important tools when patients present with ELP. When the cause is not obvious or the patient fails to respond to conservative measures, x-rays, magnetic resonance imaging (MRI), vascular studies, electromyography and nerve conduction studies, and/or intracompartmental pressure testing may be needed to find the source of the symptoms. In the text that follows, we review both common and relatively uncommon sources of ELP, using a stepwise diagnostic approach. You’ll find a diagnostic challenge, in which you can test your skills and a more comprehensive differential diagnosis in the TABLE.^1-3,5-9

Musculoskeletal injuries: Shin splints and beyond

Medial tibial stress syndrome (MTSS), commonly known as shin splints, is characterized by pain and tenderness over the posteromedial aspect of the distal tibia.³ It typically results in diffuse pain that occurs with exercise, but may persist at rest in severe cases.^3-6 Less often, localized swelling may also be present.²

MTSS accounts for between 6% and 16% of all running injuries.^2,10 It is associated with a spectrum of tibial stress injuries, including periostitis, tendinopathy, and stress reaction, with dysfunction of the tibialis posterior, tibialis anterior, and soleus muscles thought to be contributing factors.^2,11 Intrinsic factors include high body mass index (BMI), female sex, excessive internal and external hip rotation, hyperpronation, and hyper plantar flexion.^2,10,12

X-rays of the leg are typically normal in patients with MTSS and should be considered only if the clinical presentation suggests the possibility of an alternative diagnosis, such as a stress fracture or tumor.^2-4,13 Advanced imaging such as MRI or triple phase bone scans (TPBS) are useful when the diagnosis is in question and will reveal an abnormally high signal along the posterior medial tibial surface or the classic train-track appearance of nucleotide uptake in patients with MTSS.² MRI readily shows periosteal reaction and bony edema and has a sensitivity of 78% to 89% and a specificity of 33% to 100% for the diagnosis of MTSS.^14,15

While ice, NSAIDs, proper conditioning, physical therapy, and activity modification are all appropriate treatment for shin splints, none of these interventions are more effective than rest alone.

Initial management of MTSS is conservative, with the mainstay of treatment consisting of rest, ice, and nonsteroidal anti-inflammatory drugs (NSAIDs).^3,13,16 While ice, NSAIDs, proper conditioning, physical therapy to stretch and strengthen the calf musculature, rigid orthotics to correct foot hyperpronation, and activity modification are all appropriate treatments, randomized controlled trials have shown none of these interventions to be more effective than rest alone.² Non-operative treatment is usually successful, but surgery may be required for severe or refractory cases. Procedures include posteromedial fasciotomy, release of the medial soleus fascial bridge, deep compartment fasciotomy, or removal of a section of the distal tibia periosteum.^3,4

Lower extremity stress fracture. Stress fractures are caused by repetitive loading that results in microtrauma, including bony microfractures. The vast majority of cases—80% to 95% of stress fractures—affect the lower extremities, and most involve the tibia.^2-4,6,13,17 The most common presentation is an insidious onset of pain over a specific bony area with a normal appearance, although localized swelling or erythema may occasionally be present.^3,14,17,18 The pain may be reproduced or worsened by weight-bearing activities and relieved by rest.^14,18

Consider the female athlete triad. In evaluating a patient with a stress fracture, pay close attention to dietary history, BMI, and, in female athletes, take a detailed menstrual history. Such patients are at risk for amenorrhea, low bone mineral density, and nutritional deficits—the “female athlete triad,” which carries an increased risk of stress fractures.^3,14,17-19

Stress fractures can often be diagnosed with a thorough medical history and physical, with imaging used for confirmation.^6,14,17,18 Historical features of a stress fracture that may differentiate it from MTSS include pain that is unilateral and absent at rest and occurs with more prolonged activity, as well as post-exercise and/or nocturnal pain. Notable physical exam features include pain that is reproduced in a focal area with a single leg hop or percussion with a tuning fork or ultrasound.^5,11,17

Initially, sensitivity for a plain radiograph is as low as 10%.^2,11 Abnormalities on x-ray are usually seen after 2 to 8 weeks of symptoms^2,7,11 and may include a faint periosteal reaction, a fluffy area of callus, or a cortical lucency sometimes referred to as the “dreaded black line.”^3,6,17 If a radiographic exam shows evidence of a stress fracture, further imaging is typically unnecessary. MRI or TPBS is suggested, however, when x-rays appear normal but suspicion of a stress fracture remains.^3,17,18 MRI may show edema within 3 days of symptom onset and is more sensitive and specific than computed tomography (CT) or TPBS for diagnosing stress fractures of the tibia.^2,16

Treatment of tibial stress fractures is typically non-operative and consists of alterations in activity (eg, non weight-bearing), correction of nutritional deficits, such as inadequate caloric intake or too little calcium or iron, and addressing problems with footwear, training regimen, and/or running surface.^3,14,18 Fibular and posteromedial tibial stress fractures are considered low risk and heal with weight-bearing restrictions and rest, initially for a minimum of 2 to 4 weeks.³

Posteromedial tibia injuries tend to heal well because they are on the compression side of the bone. Anterior tibia stress fractures, which are located on the tension side of the bone^2,7 and account for approximately 5% of all tibia stress fractures, are more prone to non-union or progression to a complete fracture.^7,20 Thus, anterior tibia stress injuries warrant a more aggressive approach, with treatment options including non-weight bearing status that may last longer than 8 weeks, pneumatic brace casting, and/or orthopedic referral to evaluate for surgical intervention.^7,20-22 Time for radiographic evidence of healing may exceed 8 months, so early surgical intervention should be considered, especially for high-level athletes.^7,20,21

When to suspect chronic exertional compartment syndrome

Leg pain in CECS results from increased pressure within the lower extremity fascial compartments temporally related to exercise.^2,23,24 Its incidence in the general population is unknown, but CECS has been found to range from 14% to 27% in patients with previously undiagnosed leg pain^1,14,25 and to affect about a third of athletes with chronic ELP. In addition, CECS has been found in 90% of patients who have both diabetes and ELP with normal findings on vascular studies.^1,3,4,26

Pain associated with a stress fracture can typically be reproduced in a focal area with a single leg hop or percussion with a tuning fork.

The anterior compartment is most commonly affected, followed by the lateral, deep posterior, and superficial posterior compartments.^3,13,23,27 Symptoms are bilateral 60% to 95% of the time.^2,13,14,25 Factors contributing to CECS include fixed muscular compartment constraints, muscle swelling, thickened fascia, muscle hypertrophy related to resistance training, dynamic muscular contraction patterns, and low muscle capillary supply. Stretching of fascial pain receptors and pressure fibers and inadequate myocyte response to increased metabolism may play a role, as well.^14,28

The initial clinical presentation is usually predictable leg pain—ie, pain that begins at about the same time, distance, or intensity of a workout and resolves with rest; numbness and weakness may occur as the workout progresses. In time, leg pain associated with CECS may be present with everyday activity or at rest. The physical exam may be normal or reveal swelling, tenderness over the involved compartments, pain with passive digit or ankle motion, and palpable muscle herniation.¹⁴

Measurement of intracompartmental pressure before and after exercise is the gold standard for diagnosis of CECS.^2,14,27 Pre-exercise values ≥15 mm Hg and post-exercise values ≥30 mm Hg at one minute or ≥20 mm Hg at 5 minutes are all considered diagnostic of CECS,¹¹ although these widely accepted criteria for bilateral testing of all compartments yields a false-positive rate of 5%.²⁷ CECS is almost always bilateral,²⁹ and some clinicians advocate limiting the number of needle insertions by taking only post-exercise measurements and testing only symptomatic compartments in one limb.

Imaging has limited value, as both x-rays and MRIs are usually normal.¹⁴ How­ever, post-exertional T2-weighted MRI findings of muscular edema correspond to increased intracompartmental pressures, with a sensitivity of 87% and a specificity of 62%.^14,24,30,31 Infrared spectroscopy, which measures levels of oxygenated and deoxygenated blood, is sensitive for CECS when the post-exercise ratio of deoxygenated to oxygenated blood remains elevated.^14,24 Neither of these screening modalities is routinely obtained or considered diagnostic, however. Their chief role is to exclude an alternative diagnosis.¹⁴

Treatment and symptom relief. Discontinuing or modifying the aggravating activity typically brings relief of CECS. But this is not a long-term solution, as symptoms are likely to recur when the patient returns to the activity in question.¹ The definitive treatment is compartment release via fasciotomy. Success rates for anterior and lateral compartment releases are >80%.^1,28 The success of fasciotomy of posterior compartments, however, is <50%—a finding attributed to more complex anatomy, difficult visualization, and the presence of additional compartments.^1,32

When the cause is vascular

Arterial endofibrosis—the fibrotic thickening of the intima of an artery—is thought to be caused by repetitive hip flexion.⁸ This results in hyperplasia, wall thickening, and eventual stenosis of the vessel, with 90% of cases affecting the external iliac artery.^8,33 The condition is most common in activities such as cycling, but is also seen in such activities as running, skiing, soccer, and rugby. Symptoms are typically unilateral, but an estimated 15% of patients experience bilateral symptoms.^8,33

Loss of power in the affected leg, with intermittent claudication and pain due to presumed ischemia from the vascular defect, is the usual presentation, although some patients develop cramping of the buttocks and/or paresthesia of the affected leg and foot during uphill running or cycling.^8,33 The physical exam is often normal, but there may be a post-exercise arterial bruit over the femoral artery when the hip is flexed.^8,34

Consider spinal stenosis in patients who report bilateral lower extremity numbness and tingling that radiates down the legs.

Pre-exercise ankle-brachial index (ABI) <0.5 and post-exercise ABI <0.66 at one minute is suggestive of moderate arterial endofibrosis, with 90% sensitivity and 87% specificity.^8,33,34 Arterial ultrasound and color Doppler may also be used for diagnosis, but are often operator dependent. Magnetic resonance angiography (MRA), while more expensive, can detect excessive kinking or compression of the vessel and is not operator dependent.^8,33 Angioplastic balloon catheter dilation and stenting, bypass surgery, vascular reconstruction and endarterectomy with vein patch are the options for treatment. The success rates of the various interventions are unknown due to a lack of head-to-head studies and long-term follow-up.^8,33

Popliteal artery entrapment syndrome (PAES) is a constellation of symptoms caused by vascular impingement in the popliteal fossa of the knee.^8,34 The typical presenting symptoms are lower limb ischemia and pain caused by intense exercise that resolves quickly afterwards. Symptoms correlate more with the intensity than the duration of exercise.^3,8

PAES is usually caused by a variant of the gastrocnemius muscle in which a medial head passes behind the popliteal artery in males younger than 30 years.^8,33-35 Less commonly, it is the result of an overuse or acute orthopedic injury that irritates structures surrounding the popliteal fossa.^8,34 PAES affects football, basketball, and soccer players, as well as runners because of excessive dorsiflexion and plantar flexion of the ankle.^3,4

The physical exam for a patient with PAES is typically normal, but a post-exercise popliteal bruit with weak peripheral pulses may be elicited.^8,33 An ABI in the neutral, forced dorsiflexion and forced plantar flexion positions can serve as a useful screening tool. An ABI <0.9 is abnormal, with a sensitivity and specificity of 90% and 98%, respectively, for stenosis >50%.^2,36

An ankle-brachial index in the neutral, forced dorsiflexion and forced plantar flexion positions is a useful screening tool for popliteal artery entrapment syndrome.

Arteriography is the gold standard for diagnosis of PAES. Contrast arteriography is most commonly used because of its availability and cost. But MRA better differentiates functional from anatomic entrapment—a differentiation that less invasive tests, such as duplex ultrasound studies, lack the specificity to reveal.^8,34 Treatment requires either surgical removal of the offending musculotendinous structures or arterial bypass and grafting of the chronically impinged area, as conservative therapies lack efficacy.^2,8,34

Cystic adventitial disease (CAD) is the narrowing of an artery by mucoid cysts in the arterial wall or adventitia.^8,9 It is a rare condition, accounting for just 0.1% of all vascular diseases, most commonly occurring in men in their mid-40s.^8,33 CAD is thought to be the result of mucin-producing cells being haphazardly incorporated into the adventitia during arterial development. About 85% of patients whose popliteal artery is affected in this way will experience intermittent claudication with activity.^8,9

On exam, such patients often have diminished ankle-brachial pressure indices, and duplex ultrasound often reveals stenosis in the affected artery, as well as a collection of mucoid cysts in the adventitia.^8,9

Diagnosis can be confirmed by MRA.^8,37 Evidence for the treatment of CAD is largely anecdotal.⁹ Cysts may be aspirated but tend to recur, and stenting does not correct the cystic-induced narrowing of the vessel. Surgical removal of the cysts is the only successful treatment.^8,9

Neurologic causes to consider

Spinal stenosis is caused by central canal narrowing secondary to congenital abnormalities, trauma, or, most commonly, degenerative changes in the lumbar spine. Spinal stenosis is generally seen in men or women ages 50 to 70 years.³⁸ Patients experience unilateral or bilateral claudication that improves with sitting or flexion of the spine⁵ and may develop bilateral lower extremity numbness and tingling from the buttocks that radiates down the legs. Diagnosis is typically made with a combination of a lumbar x-ray and an MRI, which will show nerve compression and bony overgrowth.³⁸ CT myelogram, another imaging option, isless sensitive in the acute phase, but can be used to monitor the disease course.

Initial treatment includes physical therapy and NSAIDs.⁵ If conservative therapy fails, epidural or nerve root corticosteroid injections and surgical decompression or laminectomy are options.³⁸

Nerve entrapment is a less common source of lower extremity pain in which the superficial peroneal nerve is most often affected.^4,12,17,39 Trauma is the usual cause of nerve entrapment, but it may also be associated with overuse, most notably related to dance, soccer, or tennis.^2,14,40,41 The most likely anatomic site is where the nerve exits the deep fascia within the lateral compartment in the lower third of the leg.^39,40 Less frequently, the common peroneal nerve at the fibular neck, the saphenous nerve as it passes through Hunter’s canal, the posterior tibial nerve at the tarsal tunnel, and the sural nerve in the posterior calf may be affected.^{3,4,12,17,20,40,41} Entrapment of the peroneal nerve may be associated with activities involving repetitive inversion and eversion, such as running and cycling. Injury of the saphenous nerve is seen in sports involving repetitive knee flexion like rowing and cycling. Sural nerve entrapment is a result of crural fascia compression of the nerve during activities like running and track.^{3,14,40,42,43}

Patients typically experience burning, tingling, and radiation of pain with activity. Symptoms worsen with continued exercise. The physical exam is often normal, especially early in the disease process, but may reveal sensory loss, motor weakness, and a loss of reflexes.^2,40 Patients with superficial peroneal nerve involvement may have distal lateral leg pain that radiates into the dorsum of the foot, often exacerbated by lower leg percussion and resulting in diminished sensation.¹ Common peroneal nerve involvement may alter sensation of the lateral leg, as well, but may also cause foot drop.² The saphenous nerve can cause medial knee or leg symptoms, while the sural nerve can yield pain in the lateral ankle and foot.²

To diagnose nerve entrapment, electromyography and nerve conduction velocities at the level of the lesion may yield positive results 3 to 4 weeks after symptom onset.^2,13,40 There are wide ranges of sensitivity and specificity for these studies, but they are nonetheless considered the tests of choice for nerve entrapment.^1,44 Conservative treatment with activity modification, physical therapy, massage, and NSAIDs is often sufficient,² with surgical management warranted only for refractory cases.^2,14,40,41

CORRESPONDENCE
Jonathan A. Becker, MD, CAQSM, University of Louisville Department of Family and Geriatric Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; jon.becker@louisville@edu.

Most family physicians are accustomed to treating active patients with shin splints and stress fractures. But many are less familiar with, and slower to recognize, other sources of exertional leg pain (ELP), defined as exercise-related pain that localizes in the lower extremity distal to the knee and proximal to the talocrural joint.¹

ELP has a broad differential diagnosis that includes other musculoskeletal conditions—most notably chronic exertional compartment syndrome (CECS), which has been found to affect 33% of athletes with chronic ELP¹—as well as a number of vascular and neurologic causes.^2-4 In addition, etiologies may overlap. Greater awareness of the many causes of ELP can help you to avoid the unnecessary use of expensive diagnostic tests as well as delayed diagnosis and treatment.

A thorough medical and activity history, symptom review, and physical examination are your most important tools when patients present with ELP. When the cause is not obvious or the patient fails to respond to conservative measures, x-rays, magnetic resonance imaging (MRI), vascular studies, electromyography and nerve conduction studies, and/or intracompartmental pressure testing may be needed to find the source of the symptoms. In the text that follows, we review both common and relatively uncommon sources of ELP, using a stepwise diagnostic approach. You’ll find a diagnostic challenge, in which you can test your skills and a more comprehensive differential diagnosis in the TABLE.^1-3,5-9

Musculoskeletal injuries: Shin splints and beyond

Medial tibial stress syndrome (MTSS), commonly known as shin splints, is characterized by pain and tenderness over the posteromedial aspect of the distal tibia.³ It typically results in diffuse pain that occurs with exercise, but may persist at rest in severe cases.^3-6 Less often, localized swelling may also be present.²

MTSS accounts for between 6% and 16% of all running injuries.^2,10 It is associated with a spectrum of tibial stress injuries, including periostitis, tendinopathy, and stress reaction, with dysfunction of the tibialis posterior, tibialis anterior, and soleus muscles thought to be contributing factors.^2,11 Intrinsic factors include high body mass index (BMI), female sex, excessive internal and external hip rotation, hyperpronation, and hyper plantar flexion.^2,10,12

X-rays of the leg are typically normal in patients with MTSS and should be considered only if the clinical presentation suggests the possibility of an alternative diagnosis, such as a stress fracture or tumor.^2-4,13 Advanced imaging such as MRI or triple phase bone scans (TPBS) are useful when the diagnosis is in question and will reveal an abnormally high signal along the posterior medial tibial surface or the classic train-track appearance of nucleotide uptake in patients with MTSS.² MRI readily shows periosteal reaction and bony edema and has a sensitivity of 78% to 89% and a specificity of 33% to 100% for the diagnosis of MTSS.^14,15

While ice, NSAIDs, proper conditioning, physical therapy, and activity modification are all appropriate treatment for shin splints, none of these interventions are more effective than rest alone.

Initial management of MTSS is conservative, with the mainstay of treatment consisting of rest, ice, and nonsteroidal anti-inflammatory drugs (NSAIDs).^3,13,16 While ice, NSAIDs, proper conditioning, physical therapy to stretch and strengthen the calf musculature, rigid orthotics to correct foot hyperpronation, and activity modification are all appropriate treatments, randomized controlled trials have shown none of these interventions to be more effective than rest alone.² Non-operative treatment is usually successful, but surgery may be required for severe or refractory cases. Procedures include posteromedial fasciotomy, release of the medial soleus fascial bridge, deep compartment fasciotomy, or removal of a section of the distal tibia periosteum.^3,4

Lower extremity stress fracture. Stress fractures are caused by repetitive loading that results in microtrauma, including bony microfractures. The vast majority of cases—80% to 95% of stress fractures—affect the lower extremities, and most involve the tibia.^2-4,6,13,17 The most common presentation is an insidious onset of pain over a specific bony area with a normal appearance, although localized swelling or erythema may occasionally be present.^3,14,17,18 The pain may be reproduced or worsened by weight-bearing activities and relieved by rest.^14,18

Consider the female athlete triad. In evaluating a patient with a stress fracture, pay close attention to dietary history, BMI, and, in female athletes, take a detailed menstrual history. Such patients are at risk for amenorrhea, low bone mineral density, and nutritional deficits—the “female athlete triad,” which carries an increased risk of stress fractures.^3,14,17-19

Stress fractures can often be diagnosed with a thorough medical history and physical, with imaging used for confirmation.^6,14,17,18 Historical features of a stress fracture that may differentiate it from MTSS include pain that is unilateral and absent at rest and occurs with more prolonged activity, as well as post-exercise and/or nocturnal pain. Notable physical exam features include pain that is reproduced in a focal area with a single leg hop or percussion with a tuning fork or ultrasound.^5,11,17

Initially, sensitivity for a plain radiograph is as low as 10%.^2,11 Abnormalities on x-ray are usually seen after 2 to 8 weeks of symptoms^2,7,11 and may include a faint periosteal reaction, a fluffy area of callus, or a cortical lucency sometimes referred to as the “dreaded black line.”^3,6,17 If a radiographic exam shows evidence of a stress fracture, further imaging is typically unnecessary. MRI or TPBS is suggested, however, when x-rays appear normal but suspicion of a stress fracture remains.^3,17,18 MRI may show edema within 3 days of symptom onset and is more sensitive and specific than computed tomography (CT) or TPBS for diagnosing stress fractures of the tibia.^2,16

Treatment of tibial stress fractures is typically non-operative and consists of alterations in activity (eg, non weight-bearing), correction of nutritional deficits, such as inadequate caloric intake or too little calcium or iron, and addressing problems with footwear, training regimen, and/or running surface.^3,14,18 Fibular and posteromedial tibial stress fractures are considered low risk and heal with weight-bearing restrictions and rest, initially for a minimum of 2 to 4 weeks.³

Posteromedial tibia injuries tend to heal well because they are on the compression side of the bone. Anterior tibia stress fractures, which are located on the tension side of the bone^2,7 and account for approximately 5% of all tibia stress fractures, are more prone to non-union or progression to a complete fracture.^7,20 Thus, anterior tibia stress injuries warrant a more aggressive approach, with treatment options including non-weight bearing status that may last longer than 8 weeks, pneumatic brace casting, and/or orthopedic referral to evaluate for surgical intervention.^7,20-22 Time for radiographic evidence of healing may exceed 8 months, so early surgical intervention should be considered, especially for high-level athletes.^7,20,21

When to suspect chronic exertional compartment syndrome

Leg pain in CECS results from increased pressure within the lower extremity fascial compartments temporally related to exercise.^2,23,24 Its incidence in the general population is unknown, but CECS has been found to range from 14% to 27% in patients with previously undiagnosed leg pain^1,14,25 and to affect about a third of athletes with chronic ELP. In addition, CECS has been found in 90% of patients who have both diabetes and ELP with normal findings on vascular studies.^1,3,4,26

Pain associated with a stress fracture can typically be reproduced in a focal area with a single leg hop or percussion with a tuning fork.

The anterior compartment is most commonly affected, followed by the lateral, deep posterior, and superficial posterior compartments.^3,13,23,27 Symptoms are bilateral 60% to 95% of the time.^2,13,14,25 Factors contributing to CECS include fixed muscular compartment constraints, muscle swelling, thickened fascia, muscle hypertrophy related to resistance training, dynamic muscular contraction patterns, and low muscle capillary supply. Stretching of fascial pain receptors and pressure fibers and inadequate myocyte response to increased metabolism may play a role, as well.^14,28

The initial clinical presentation is usually predictable leg pain—ie, pain that begins at about the same time, distance, or intensity of a workout and resolves with rest; numbness and weakness may occur as the workout progresses. In time, leg pain associated with CECS may be present with everyday activity or at rest. The physical exam may be normal or reveal swelling, tenderness over the involved compartments, pain with passive digit or ankle motion, and palpable muscle herniation.¹⁴

Measurement of intracompartmental pressure before and after exercise is the gold standard for diagnosis of CECS.^2,14,27 Pre-exercise values ≥15 mm Hg and post-exercise values ≥30 mm Hg at one minute or ≥20 mm Hg at 5 minutes are all considered diagnostic of CECS,¹¹ although these widely accepted criteria for bilateral testing of all compartments yields a false-positive rate of 5%.²⁷ CECS is almost always bilateral,²⁹ and some clinicians advocate limiting the number of needle insertions by taking only post-exercise measurements and testing only symptomatic compartments in one limb.

Imaging has limited value, as both x-rays and MRIs are usually normal.¹⁴ How­ever, post-exertional T2-weighted MRI findings of muscular edema correspond to increased intracompartmental pressures, with a sensitivity of 87% and a specificity of 62%.^14,24,30,31 Infrared spectroscopy, which measures levels of oxygenated and deoxygenated blood, is sensitive for CECS when the post-exercise ratio of deoxygenated to oxygenated blood remains elevated.^14,24 Neither of these screening modalities is routinely obtained or considered diagnostic, however. Their chief role is to exclude an alternative diagnosis.¹⁴

Treatment and symptom relief. Discontinuing or modifying the aggravating activity typically brings relief of CECS. But this is not a long-term solution, as symptoms are likely to recur when the patient returns to the activity in question.¹ The definitive treatment is compartment release via fasciotomy. Success rates for anterior and lateral compartment releases are >80%.^1,28 The success of fasciotomy of posterior compartments, however, is <50%—a finding attributed to more complex anatomy, difficult visualization, and the presence of additional compartments.^1,32

When the cause is vascular

Arterial endofibrosis—the fibrotic thickening of the intima of an artery—is thought to be caused by repetitive hip flexion.⁸ This results in hyperplasia, wall thickening, and eventual stenosis of the vessel, with 90% of cases affecting the external iliac artery.^8,33 The condition is most common in activities such as cycling, but is also seen in such activities as running, skiing, soccer, and rugby. Symptoms are typically unilateral, but an estimated 15% of patients experience bilateral symptoms.^8,33

Loss of power in the affected leg, with intermittent claudication and pain due to presumed ischemia from the vascular defect, is the usual presentation, although some patients develop cramping of the buttocks and/or paresthesia of the affected leg and foot during uphill running or cycling.^8,33 The physical exam is often normal, but there may be a post-exercise arterial bruit over the femoral artery when the hip is flexed.^8,34

Consider spinal stenosis in patients who report bilateral lower extremity numbness and tingling that radiates down the legs.

Pre-exercise ankle-brachial index (ABI) <0.5 and post-exercise ABI <0.66 at one minute is suggestive of moderate arterial endofibrosis, with 90% sensitivity and 87% specificity.^8,33,34 Arterial ultrasound and color Doppler may also be used for diagnosis, but are often operator dependent. Magnetic resonance angiography (MRA), while more expensive, can detect excessive kinking or compression of the vessel and is not operator dependent.^8,33 Angioplastic balloon catheter dilation and stenting, bypass surgery, vascular reconstruction and endarterectomy with vein patch are the options for treatment. The success rates of the various interventions are unknown due to a lack of head-to-head studies and long-term follow-up.^8,33

Popliteal artery entrapment syndrome (PAES) is a constellation of symptoms caused by vascular impingement in the popliteal fossa of the knee.^8,34 The typical presenting symptoms are lower limb ischemia and pain caused by intense exercise that resolves quickly afterwards. Symptoms correlate more with the intensity than the duration of exercise.^3,8

PAES is usually caused by a variant of the gastrocnemius muscle in which a medial head passes behind the popliteal artery in males younger than 30 years.^8,33-35 Less commonly, it is the result of an overuse or acute orthopedic injury that irritates structures surrounding the popliteal fossa.^8,34 PAES affects football, basketball, and soccer players, as well as runners because of excessive dorsiflexion and plantar flexion of the ankle.^3,4

The physical exam for a patient with PAES is typically normal, but a post-exercise popliteal bruit with weak peripheral pulses may be elicited.^8,33 An ABI in the neutral, forced dorsiflexion and forced plantar flexion positions can serve as a useful screening tool. An ABI <0.9 is abnormal, with a sensitivity and specificity of 90% and 98%, respectively, for stenosis >50%.^2,36

An ankle-brachial index in the neutral, forced dorsiflexion and forced plantar flexion positions is a useful screening tool for popliteal artery entrapment syndrome.

Arteriography is the gold standard for diagnosis of PAES. Contrast arteriography is most commonly used because of its availability and cost. But MRA better differentiates functional from anatomic entrapment—a differentiation that less invasive tests, such as duplex ultrasound studies, lack the specificity to reveal.^8,34 Treatment requires either surgical removal of the offending musculotendinous structures or arterial bypass and grafting of the chronically impinged area, as conservative therapies lack efficacy.^2,8,34

Cystic adventitial disease (CAD) is the narrowing of an artery by mucoid cysts in the arterial wall or adventitia.^8,9 It is a rare condition, accounting for just 0.1% of all vascular diseases, most commonly occurring in men in their mid-40s.^8,33 CAD is thought to be the result of mucin-producing cells being haphazardly incorporated into the adventitia during arterial development. About 85% of patients whose popliteal artery is affected in this way will experience intermittent claudication with activity.^8,9

On exam, such patients often have diminished ankle-brachial pressure indices, and duplex ultrasound often reveals stenosis in the affected artery, as well as a collection of mucoid cysts in the adventitia.^8,9

Diagnosis can be confirmed by MRA.^8,37 Evidence for the treatment of CAD is largely anecdotal.⁹ Cysts may be aspirated but tend to recur, and stenting does not correct the cystic-induced narrowing of the vessel. Surgical removal of the cysts is the only successful treatment.^8,9

Neurologic causes to consider

Spinal stenosis is caused by central canal narrowing secondary to congenital abnormalities, trauma, or, most commonly, degenerative changes in the lumbar spine. Spinal stenosis is generally seen in men or women ages 50 to 70 years.³⁸ Patients experience unilateral or bilateral claudication that improves with sitting or flexion of the spine⁵ and may develop bilateral lower extremity numbness and tingling from the buttocks that radiates down the legs. Diagnosis is typically made with a combination of a lumbar x-ray and an MRI, which will show nerve compression and bony overgrowth.³⁸ CT myelogram, another imaging option, isless sensitive in the acute phase, but can be used to monitor the disease course.

Initial treatment includes physical therapy and NSAIDs.⁵ If conservative therapy fails, epidural or nerve root corticosteroid injections and surgical decompression or laminectomy are options.³⁸

Nerve entrapment is a less common source of lower extremity pain in which the superficial peroneal nerve is most often affected.^4,12,17,39 Trauma is the usual cause of nerve entrapment, but it may also be associated with overuse, most notably related to dance, soccer, or tennis.^2,14,40,41 The most likely anatomic site is where the nerve exits the deep fascia within the lateral compartment in the lower third of the leg.^39,40 Less frequently, the common peroneal nerve at the fibular neck, the saphenous nerve as it passes through Hunter’s canal, the posterior tibial nerve at the tarsal tunnel, and the sural nerve in the posterior calf may be affected.^{3,4,12,17,20,40,41} Entrapment of the peroneal nerve may be associated with activities involving repetitive inversion and eversion, such as running and cycling. Injury of the saphenous nerve is seen in sports involving repetitive knee flexion like rowing and cycling. Sural nerve entrapment is a result of crural fascia compression of the nerve during activities like running and track.^{3,14,40,42,43}

Patients typically experience burning, tingling, and radiation of pain with activity. Symptoms worsen with continued exercise. The physical exam is often normal, especially early in the disease process, but may reveal sensory loss, motor weakness, and a loss of reflexes.^2,40 Patients with superficial peroneal nerve involvement may have distal lateral leg pain that radiates into the dorsum of the foot, often exacerbated by lower leg percussion and resulting in diminished sensation.¹ Common peroneal nerve involvement may alter sensation of the lateral leg, as well, but may also cause foot drop.² The saphenous nerve can cause medial knee or leg symptoms, while the sural nerve can yield pain in the lateral ankle and foot.²

To diagnose nerve entrapment, electromyography and nerve conduction velocities at the level of the lesion may yield positive results 3 to 4 weeks after symptom onset.^2,13,40 There are wide ranges of sensitivity and specificity for these studies, but they are nonetheless considered the tests of choice for nerve entrapment.^1,44 Conservative treatment with activity modification, physical therapy, massage, and NSAIDs is often sufficient,² with surgical management warranted only for refractory cases.^2,14,40,41

CORRESPONDENCE
Jonathan A. Becker, MD, CAQSM, University of Louisville Department of Family and Geriatric Medicine, 201 Abraham Flexner Way, Suite 690, Louisville, KY 40202; jon.becker@louisville@edu.

About 27 million Americans undergo surgery every year¹ and before doing so, they turn to you—their primary care physician—or their cardiologist for a preoperative evaluation. Of course, the goal of this evaluation is to determine an individual patient’s risk and compare it to procedural averages in an effort to identify opportunities for risk mitigation. But the preoperative evaluation is also an opportunity to make recommendations regarding perioperative management of medications. And certainly we want to conduct these evaluations in a way that is both expeditious and in keeping with the latest guidelines.

Current guidelines for preoperative evaluations are less complicated than they used to be and focus on cardiac and pulmonary risk stratification. While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the preop equation. In the review that follows, we present a simple algorithm (FIGURE 1^2-6) that we developed that can be completed in a single visit.

Cardiac assessment: A risk calculator is the primary tool

Cardiac risk estimation is perhaps the most important element in determining a patient’s overall surgical risk. But before you begin, you'll need to determine whether the preoperative evaluation of the patient is best handled by you or a specialist. Current guidelines recommend preoperative evaluation by a specialist when a patient has certain conditions, such as moderate or greater valvular stenosis/regurgitation, a cardiac implantable electronic device, pulmonary hypertension, congenital heart disease, or severe systemic disease.²

If these conditions are not present (and an immediate referral is not required), you can turn your attention to the cardiac assessment. The first step is to determine which cardiac risk calculator you’d like to use. In its comprehensive guideline on perioperative cardiovascular evaluation, the American College of Cardiology/American Heart Association (ACC/AHA) recommends the use of one of the 2 calculators described below.²

Revised Cardiac Risk Index. The most well-known cardiac risk calculator is the 6-element Revised Cardiac Risk Index (RCRI) (TABLE 1).⁷ Published in 1999, the RCRI was derived from a cohort of 2800 patients, verified in 1400 patients, and has been validated in numerous studies.² Each element increases the odds of a cardiac complication by a factor of 2 to 3, and more than one positive response indicates the patient is at high risk for complications.⁷

While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the equation.

The ACS NSQIP risk calculator has been criticized because it has not been validated in a group separate from the initial patient population used in its development.² Another criticism is the inclusion of the American Society of Anesthesiologists' (ASA) classification of the overall health of the patient, a simple yet subjective and unreliable method of patient characterization.²

Choosing a calculator. The ACS NSQIP calculator may be more useful for primary care physicians because it provides individualized risks for numerous complications and is easy to use. The output page can be printed as documentation of the preoperative evaluation, and is useful for counseling patients about reconsideration of surgery or risk-reduction strategies. The RCRI is also simple to use, but considers only cardiac risk. Although the RCRI has been validated in numerous studies, the ACS NSQIP was derived from a more substantial 1.4 million patients.

The next step in the preoperative evaluation process is to calculate your patient’s risk score and determine whether it is low or high. If the risk is determined to be low—either an RCRI score <2 or an ACS NSQIP cardiac complication risk <1%—the patient can be referred to surgery without further evaluation.²

If the patient has a functional status of >4 METs, refer him or her for surgery without further evaluation.

If the calculator suggests higher risk, the patient’s functional status should be assessed. If the patient has a functional status of >4 metabolic equivalents (METs), then the patient can be recommended for surgery without further evaluation.² Examples of activities that are greater than 4 METs are yard work such as raking leaves, weeding, or pushing a power mower; sexual relations; climbing a flight of stairs; walking up a hill; and participating in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football.⁹

Patient can’t perform >4 METs? If the patient does not have a functional capacity of >4 METs, further risk stratification should be considered if the results would change management.² Prior guidelines recommended either perioperative beta-blockers to mitigate risk or coronary interventions, but both are controversial due to lack of proven benefit.

Perioperative beta-blocker use. A recommendation to consider starting beta-blockers at least one day prior to surgery remains in the 2014 ACC/AHA guidelines for patients with 3 or more RCRI risk factors.² But a group of studies supporting beta-blocker use has been discredited due to serious flaws and fabricated data. At the same time, a large study arguing against perioperative beta-blockers has been criticized for starting high doses of beta-blockers on the day of surgery.^2,10,11 In the end, mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.²

Stress testing is of questionable value. A patient with high cardiac risk (as evaluated with a calculator) may need to forego the surgical procedure or undergo a modified procedure. Alternatively, he or she may need to be referred to a cardiologist for consultation and possible pharmacologic nuclear stress testing. Although a normal stress test has a high negative predictive value, an abnormal test often leads to percutaneous coronary intervention or bypass surgery, and neither has been shown to reduce cardiac surgical risk.² Percutaneous coronary interventions require a period of dual antiplatelet therapy, delaying surgery for unproven benefit.²

EKGs and echocardiograms are of limited use. An anesthesia group or surgical center will often require an electrocardiogram (EKG) as part of a preoperative evaluation, but preoperative evaluation by EKG or echocardiogram is controversial due to unproven benefits and potential risks. The 2014 ACC/AHA guidelines recommend against a 12-lead EKG for patients with low cardiac risk using the RCRI or ACS NSQIP or those who are having a low-risk procedure, such as endoscopy or cataract surgery.² The United States Preventive Health Services Task Force also recommends against screening low-risk patients and says that screening EKGs and stress testing in asymptomatic medium- to high-risk patients is of undetermined value.¹² They noted no evidence of benefit from resting or exercise EKG, with harm from a 1.7% complication rate of angiography, which is performed after up to 2.9% of exercise EKG testing.¹²

Mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.

There are no recommendations for preoperative echocardiogram in the asymptomatic patient. Only unexplained dyspnea or other clinical signs of heart failure require an echocardiogram. For patients with known heart failure that is clinically stable, the ACC/AHA guidelines suggest that an echocardiogram should be performed within the year prior to surgery, although this is based on expert opinion.²

Because of the controversy over both coronary interventions and perioperative beta-blocker therapy, consider cardiology referral for a patient with poor functional activity level who does not meet low-risk criteria. While stress testing is acceptable, it may not lead to improved patient outcomes.

Optimize preventive care

Begin by ensuring that blood pressure (BP) and cholesterol are managed according to ACC/AHA guidelines. Then consider whether to start preoperative medications. You'll also want to screen for sleep apnea and discuss smoking status and cessation, if appropriate.

Initiate medications preoperatively?

In addition to having value as long-term primary prevention, there is some evidence that statins help prevent cardiac events during surgery. A randomized trial of over 200 vascular surgery patients showed that starting statins an average of 30 days prior to surgery significantly reduced cardiac complications.¹³ Another systematic review demonstrated that preoperative statins significantly reduce acute kidney injury from surgery.¹⁴

Unlike statins, aspirin started prior to surgery does not confer benefit. Aspirin was shown to significantly increase bleeding risk without improving cardiac outcomes in a large trial.¹⁵

Screen for sleep apnea

Sleep apnea increases the rate of respiratory failure between 2 and 3 times and the rate of cardiac complications about 1.5 times.¹⁶ This is a potentially correctable risk factor. The European Society of Anaesthesiology recommends clinical screening for obstructive sleep apnea using the STOP-Bang screening tool⁵ (TABLE 2⁴). For its part, the ASA combines screening questions from the STOP-Bang screening questionnaire with a review of the medical record and physical exam, because the STOP-Bang questionnaire alone has an insufficient negative predictive value, ranging from 30% and 82%.⁶ Obstructive sleep apnea is not addressed on published pulmonary and cardiac risk tools.^2,3,7,8

Is the patient a smoker?

Smoking is a reversible risk factor for pulmonary, cardiac, and infectious complications, as well as overall mortality. Perioperative smoking cessation counseling has been complicated by concerns that stopping smoking within 8 weeks of surgery might worsen postoperative outcomes. A study that looked at intraoperative sputum retrieved via tracheal suction showed that patients who had stopped smoking for 2 months or more prior to surgery had the same amount of sputum as non-smokers, while those that quit smoking <2 months before surgery were more likely to have increased intraoperative sputum volume.¹⁸ This study did not demonstrate a difference in postoperative pulmonary complications, likely because it included patients receiving minor surgeries only. But based on this study, a cessation period of 2 months was often recommended.

A recent systematic review showed that smoking cessation shortly before surgery does not increase risk.¹⁹ In fact, although the review did not show a statistically significant reduction in postoperative complications among recent quitters as compared with continued smokers, there was a trend toward a reduction in overall complications with only a slight increase in pulmonary complications.¹⁹

Address potential pulmonary complications

In addition to screening for issues that could lead to cardiac complications, it’s important to address the potential for pulmonary complications. Postoperative pulmonary complications are at least as common as cardiac complications, and include all possible respiratory related outcomes of surgery, from pneumonia to respiratory failure.

During the preoperative evaluation, verify that BP and cholesterol are managed per ACC/AHA guidelines.

The seminal study on postoperative pulmonary complications is a systematic review published in 2006, which showed that the most important risk factors were surgery type, advanced age, ASA classification of overall health ≥II, and congestive heart failure.³ Chronic lung diseases and cigarette use were less predictive of pulmonary issues. All of these factors are included in the ACS NSQIP risk calculator.

One aspect of the preoperative evaluation that should not be overlooked is a thorough medication reconciliation. Primary care providers can support the operative team by recommending medication adjustments prior to surgery. Several classes of medications have specific perioperative recommendations, which are summarized here.

Hypertension medications

• Beta-blockers. A patient who regularly takes a beta-blocker should continue the medication on the day of surgery and restart after surgery.^2,20
• Calcium channel blockers. Calcium channel blockers can be continued through the day of surgery.^2,20
• Renin-angiotensin system antagonists. Given the increased risk of hypotension following anesthesia induction, have patients refrain from taking angiotensin-converting enzyme inhibitors and angiotensin receptor blocker medications for at least 10 hours prior to surgery.²⁰
• Diuretics. Diuretics can be given on the day of surgery, although they increase the risk of hypovolemia and electrolyte disturbances.²⁰

Diabetes medications

• Insulin. For patients with type I diabetes, recommend basal insulin of 0.2 to 0.3 units/kg/day of long-acting insulin.²¹ If the patient is using an insulin pump, basal rate should be continued. For patients with type 2 diabetes, the simplest method is to use one-half the normal long-acting insulin dose on the morning of surgery.²²
• Metformin. Discontinue metformin 24 hours prior to surgery because of the risk for lactic acidosis.^21,22 While the risk of lactic acidosis from metformin is low, mortality rates as high as 50% have been documented after lactic acidosis occurred with similar medications.²²
• Sulfonylureas. Sulfonylureas should be held on the day of surgery due to the risk of hypoglycemia and a possible increased risk of ischemia.^21,22
• Thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 agonists. All should be held on the day of surgery.²¹

Anticoagulant medications

Whether patients quit smoking less than or more than 2 months before surgery is less important than that they quit.

• Vitamin K antagonists (warfarin). Discontinue warfarin 5 days prior to the procedure. The half-life is approximately 40 hours, requiring at least 5 days for the anticoagulant effect to be eliminated from the body.²³ Use of bridging therapy with regular- or low-molecular weight heparin remains controversial due to increased surgical bleeding risk without evidence of a decrease in cardiovascular events.²⁴ The patient’s risks of stroke and venous thromboembolism should be taken into account when deciding whether to use bridging therapy or not.
• Factor Xa inhibitor. Management of factor Xa inhibitors (rivaroxaban, apixaban) depends on the bleeding risk of the surgery and the patient’s renal function.^24,25 For instance, a patient undergoing cataract surgery (low risk) needs a shorter cessation time than a patient undergoing hip arthroplasty (high risk). Discontinuation times are listed in TABLE 3.²⁴
• Direct thrombin inhibitor. Management of direct thrombin inhibitors (dabigatran) is also dependent on surgical bleeding risk and renal function (TABLE 3).^23,24
• Aspirin, clopidogrel, ticlopidine, prasugrel. All should be stopped 7 to 10 days prior to surgery to allow new platelet growth. Low-dose aspirin for secondary prevention of cardiovascular disease or primary prevention in a high-risk patient can be continued through surgery.²³

Other

• Corticosteroids. Recent evidence suggests that stress-dose steroids are not needed to prevent adrenal insufficiency in patients taking corticosteroids chronically.²⁶ These patients should continue maintenance therapy at regular dosing.^26,27 Stress dosing of corticosteroids is only required when a patient has signs of adrenal insufficiency.²⁶
• Statins. Statin medications should be continued on the day of surgery.²
• Nonsteroidal anti-inflammatory drugs. NSAIDs should be stopped 5 days prior to surgery to reverse antiplatelet effects.²³

CORRESPONDENCE
CDR Michael J. Arnold, Naval Hospital, 2080 Child Street, Jacksonville, FL 32214; [email protected].

ACKNOWLEDGEMENT
The authors thank CDR Kristian Sanchack and LCDR Dustin Smith for their assistance with this manuscript.

About 27 million Americans undergo surgery every year¹ and before doing so, they turn to you—their primary care physician—or their cardiologist for a preoperative evaluation. Of course, the goal of this evaluation is to determine an individual patient’s risk and compare it to procedural averages in an effort to identify opportunities for risk mitigation. But the preoperative evaluation is also an opportunity to make recommendations regarding perioperative management of medications. And certainly we want to conduct these evaluations in a way that is both expeditious and in keeping with the latest guidelines.

Current guidelines for preoperative evaluations are less complicated than they used to be and focus on cardiac and pulmonary risk stratification. While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the preop equation. In the review that follows, we present a simple algorithm (FIGURE 1^2-6) that we developed that can be completed in a single visit.

Cardiac assessment: A risk calculator is the primary tool

Cardiac risk estimation is perhaps the most important element in determining a patient’s overall surgical risk. But before you begin, you'll need to determine whether the preoperative evaluation of the patient is best handled by you or a specialist. Current guidelines recommend preoperative evaluation by a specialist when a patient has certain conditions, such as moderate or greater valvular stenosis/regurgitation, a cardiac implantable electronic device, pulmonary hypertension, congenital heart disease, or severe systemic disease.²

If these conditions are not present (and an immediate referral is not required), you can turn your attention to the cardiac assessment. The first step is to determine which cardiac risk calculator you’d like to use. In its comprehensive guideline on perioperative cardiovascular evaluation, the American College of Cardiology/American Heart Association (ACC/AHA) recommends the use of one of the 2 calculators described below.²

Revised Cardiac Risk Index. The most well-known cardiac risk calculator is the 6-element Revised Cardiac Risk Index (RCRI) (TABLE 1).⁷ Published in 1999, the RCRI was derived from a cohort of 2800 patients, verified in 1400 patients, and has been validated in numerous studies.² Each element increases the odds of a cardiac complication by a factor of 2 to 3, and more than one positive response indicates the patient is at high risk for complications.⁷

While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the equation.

The ACS NSQIP risk calculator has been criticized because it has not been validated in a group separate from the initial patient population used in its development.² Another criticism is the inclusion of the American Society of Anesthesiologists' (ASA) classification of the overall health of the patient, a simple yet subjective and unreliable method of patient characterization.²

Choosing a calculator. The ACS NSQIP calculator may be more useful for primary care physicians because it provides individualized risks for numerous complications and is easy to use. The output page can be printed as documentation of the preoperative evaluation, and is useful for counseling patients about reconsideration of surgery or risk-reduction strategies. The RCRI is also simple to use, but considers only cardiac risk. Although the RCRI has been validated in numerous studies, the ACS NSQIP was derived from a more substantial 1.4 million patients.

The next step in the preoperative evaluation process is to calculate your patient’s risk score and determine whether it is low or high. If the risk is determined to be low—either an RCRI score <2 or an ACS NSQIP cardiac complication risk <1%—the patient can be referred to surgery without further evaluation.²

If the patient has a functional status of >4 METs, refer him or her for surgery without further evaluation.

If the calculator suggests higher risk, the patient’s functional status should be assessed. If the patient has a functional status of >4 metabolic equivalents (METs), then the patient can be recommended for surgery without further evaluation.² Examples of activities that are greater than 4 METs are yard work such as raking leaves, weeding, or pushing a power mower; sexual relations; climbing a flight of stairs; walking up a hill; and participating in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football.⁹

Patient can’t perform >4 METs? If the patient does not have a functional capacity of >4 METs, further risk stratification should be considered if the results would change management.² Prior guidelines recommended either perioperative beta-blockers to mitigate risk or coronary interventions, but both are controversial due to lack of proven benefit.

Perioperative beta-blocker use. A recommendation to consider starting beta-blockers at least one day prior to surgery remains in the 2014 ACC/AHA guidelines for patients with 3 or more RCRI risk factors.² But a group of studies supporting beta-blocker use has been discredited due to serious flaws and fabricated data. At the same time, a large study arguing against perioperative beta-blockers has been criticized for starting high doses of beta-blockers on the day of surgery.^2,10,11 In the end, mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.²

Stress testing is of questionable value. A patient with high cardiac risk (as evaluated with a calculator) may need to forego the surgical procedure or undergo a modified procedure. Alternatively, he or she may need to be referred to a cardiologist for consultation and possible pharmacologic nuclear stress testing. Although a normal stress test has a high negative predictive value, an abnormal test often leads to percutaneous coronary intervention or bypass surgery, and neither has been shown to reduce cardiac surgical risk.² Percutaneous coronary interventions require a period of dual antiplatelet therapy, delaying surgery for unproven benefit.²

EKGs and echocardiograms are of limited use. An anesthesia group or surgical center will often require an electrocardiogram (EKG) as part of a preoperative evaluation, but preoperative evaluation by EKG or echocardiogram is controversial due to unproven benefits and potential risks. The 2014 ACC/AHA guidelines recommend against a 12-lead EKG for patients with low cardiac risk using the RCRI or ACS NSQIP or those who are having a low-risk procedure, such as endoscopy or cataract surgery.² The United States Preventive Health Services Task Force also recommends against screening low-risk patients and says that screening EKGs and stress testing in asymptomatic medium- to high-risk patients is of undetermined value.¹² They noted no evidence of benefit from resting or exercise EKG, with harm from a 1.7% complication rate of angiography, which is performed after up to 2.9% of exercise EKG testing.¹²

Mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.

There are no recommendations for preoperative echocardiogram in the asymptomatic patient. Only unexplained dyspnea or other clinical signs of heart failure require an echocardiogram. For patients with known heart failure that is clinically stable, the ACC/AHA guidelines suggest that an echocardiogram should be performed within the year prior to surgery, although this is based on expert opinion.²

Because of the controversy over both coronary interventions and perioperative beta-blocker therapy, consider cardiology referral for a patient with poor functional activity level who does not meet low-risk criteria. While stress testing is acceptable, it may not lead to improved patient outcomes.

Optimize preventive care

Begin by ensuring that blood pressure (BP) and cholesterol are managed according to ACC/AHA guidelines. Then consider whether to start preoperative medications. You'll also want to screen for sleep apnea and discuss smoking status and cessation, if appropriate.

Initiate medications preoperatively?

In addition to having value as long-term primary prevention, there is some evidence that statins help prevent cardiac events during surgery. A randomized trial of over 200 vascular surgery patients showed that starting statins an average of 30 days prior to surgery significantly reduced cardiac complications.¹³ Another systematic review demonstrated that preoperative statins significantly reduce acute kidney injury from surgery.¹⁴

Unlike statins, aspirin started prior to surgery does not confer benefit. Aspirin was shown to significantly increase bleeding risk without improving cardiac outcomes in a large trial.¹⁵

Screen for sleep apnea

Sleep apnea increases the rate of respiratory failure between 2 and 3 times and the rate of cardiac complications about 1.5 times.¹⁶ This is a potentially correctable risk factor. The European Society of Anaesthesiology recommends clinical screening for obstructive sleep apnea using the STOP-Bang screening tool⁵ (TABLE 2⁴). For its part, the ASA combines screening questions from the STOP-Bang screening questionnaire with a review of the medical record and physical exam, because the STOP-Bang questionnaire alone has an insufficient negative predictive value, ranging from 30% and 82%.⁶ Obstructive sleep apnea is not addressed on published pulmonary and cardiac risk tools.^2,3,7,8

Is the patient a smoker?

Smoking is a reversible risk factor for pulmonary, cardiac, and infectious complications, as well as overall mortality. Perioperative smoking cessation counseling has been complicated by concerns that stopping smoking within 8 weeks of surgery might worsen postoperative outcomes. A study that looked at intraoperative sputum retrieved via tracheal suction showed that patients who had stopped smoking for 2 months or more prior to surgery had the same amount of sputum as non-smokers, while those that quit smoking <2 months before surgery were more likely to have increased intraoperative sputum volume.¹⁸ This study did not demonstrate a difference in postoperative pulmonary complications, likely because it included patients receiving minor surgeries only. But based on this study, a cessation period of 2 months was often recommended.

A recent systematic review showed that smoking cessation shortly before surgery does not increase risk.¹⁹ In fact, although the review did not show a statistically significant reduction in postoperative complications among recent quitters as compared with continued smokers, there was a trend toward a reduction in overall complications with only a slight increase in pulmonary complications.¹⁹

Address potential pulmonary complications

In addition to screening for issues that could lead to cardiac complications, it’s important to address the potential for pulmonary complications. Postoperative pulmonary complications are at least as common as cardiac complications, and include all possible respiratory related outcomes of surgery, from pneumonia to respiratory failure.

During the preoperative evaluation, verify that BP and cholesterol are managed per ACC/AHA guidelines.

The seminal study on postoperative pulmonary complications is a systematic review published in 2006, which showed that the most important risk factors were surgery type, advanced age, ASA classification of overall health ≥II, and congestive heart failure.³ Chronic lung diseases and cigarette use were less predictive of pulmonary issues. All of these factors are included in the ACS NSQIP risk calculator.

One aspect of the preoperative evaluation that should not be overlooked is a thorough medication reconciliation. Primary care providers can support the operative team by recommending medication adjustments prior to surgery. Several classes of medications have specific perioperative recommendations, which are summarized here.

Hypertension medications

• Beta-blockers. A patient who regularly takes a beta-blocker should continue the medication on the day of surgery and restart after surgery.^2,20
• Calcium channel blockers. Calcium channel blockers can be continued through the day of surgery.^2,20
• Renin-angiotensin system antagonists. Given the increased risk of hypotension following anesthesia induction, have patients refrain from taking angiotensin-converting enzyme inhibitors and angiotensin receptor blocker medications for at least 10 hours prior to surgery.²⁰
• Diuretics. Diuretics can be given on the day of surgery, although they increase the risk of hypovolemia and electrolyte disturbances.²⁰

Diabetes medications

• Insulin. For patients with type I diabetes, recommend basal insulin of 0.2 to 0.3 units/kg/day of long-acting insulin.²¹ If the patient is using an insulin pump, basal rate should be continued. For patients with type 2 diabetes, the simplest method is to use one-half the normal long-acting insulin dose on the morning of surgery.²²
• Metformin. Discontinue metformin 24 hours prior to surgery because of the risk for lactic acidosis.^21,22 While the risk of lactic acidosis from metformin is low, mortality rates as high as 50% have been documented after lactic acidosis occurred with similar medications.²²
• Sulfonylureas. Sulfonylureas should be held on the day of surgery due to the risk of hypoglycemia and a possible increased risk of ischemia.^21,22
• Thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 agonists. All should be held on the day of surgery.²¹

Anticoagulant medications

Whether patients quit smoking less than or more than 2 months before surgery is less important than that they quit.

• Vitamin K antagonists (warfarin). Discontinue warfarin 5 days prior to the procedure. The half-life is approximately 40 hours, requiring at least 5 days for the anticoagulant effect to be eliminated from the body.²³ Use of bridging therapy with regular- or low-molecular weight heparin remains controversial due to increased surgical bleeding risk without evidence of a decrease in cardiovascular events.²⁴ The patient’s risks of stroke and venous thromboembolism should be taken into account when deciding whether to use bridging therapy or not.
• Factor Xa inhibitor. Management of factor Xa inhibitors (rivaroxaban, apixaban) depends on the bleeding risk of the surgery and the patient’s renal function.^24,25 For instance, a patient undergoing cataract surgery (low risk) needs a shorter cessation time than a patient undergoing hip arthroplasty (high risk). Discontinuation times are listed in TABLE 3.²⁴
• Direct thrombin inhibitor. Management of direct thrombin inhibitors (dabigatran) is also dependent on surgical bleeding risk and renal function (TABLE 3).^23,24
• Aspirin, clopidogrel, ticlopidine, prasugrel. All should be stopped 7 to 10 days prior to surgery to allow new platelet growth. Low-dose aspirin for secondary prevention of cardiovascular disease or primary prevention in a high-risk patient can be continued through surgery.²³

Other

• Corticosteroids. Recent evidence suggests that stress-dose steroids are not needed to prevent adrenal insufficiency in patients taking corticosteroids chronically.²⁶ These patients should continue maintenance therapy at regular dosing.^26,27 Stress dosing of corticosteroids is only required when a patient has signs of adrenal insufficiency.²⁶
• Statins. Statin medications should be continued on the day of surgery.²
• Nonsteroidal anti-inflammatory drugs. NSAIDs should be stopped 5 days prior to surgery to reverse antiplatelet effects.²³

CORRESPONDENCE
CDR Michael J. Arnold, Naval Hospital, 2080 Child Street, Jacksonville, FL 32214; [email protected].

ACKNOWLEDGEMENT
The authors thank CDR Kristian Sanchack and LCDR Dustin Smith for their assistance with this manuscript.

About 27 million Americans undergo surgery every year¹ and before doing so, they turn to you—their primary care physician—or their cardiologist for a preoperative evaluation. Of course, the goal of this evaluation is to determine an individual patient’s risk and compare it to procedural averages in an effort to identify opportunities for risk mitigation. But the preoperative evaluation is also an opportunity to make recommendations regarding perioperative management of medications. And certainly we want to conduct these evaluations in a way that is both expeditious and in keeping with the latest guidelines.

Current guidelines for preoperative evaluations are less complicated than they used to be and focus on cardiac and pulmonary risk stratification. While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the preop equation. In the review that follows, we present a simple algorithm (FIGURE 1^2-6) that we developed that can be completed in a single visit.

Cardiac assessment: A risk calculator is the primary tool

Cardiac risk estimation is perhaps the most important element in determining a patient’s overall surgical risk. But before you begin, you'll need to determine whether the preoperative evaluation of the patient is best handled by you or a specialist. Current guidelines recommend preoperative evaluation by a specialist when a patient has certain conditions, such as moderate or greater valvular stenosis/regurgitation, a cardiac implantable electronic device, pulmonary hypertension, congenital heart disease, or severe systemic disease.²

If these conditions are not present (and an immediate referral is not required), you can turn your attention to the cardiac assessment. The first step is to determine which cardiac risk calculator you’d like to use. In its comprehensive guideline on perioperative cardiovascular evaluation, the American College of Cardiology/American Heart Association (ACC/AHA) recommends the use of one of the 2 calculators described below.²

Revised Cardiac Risk Index. The most well-known cardiac risk calculator is the 6-element Revised Cardiac Risk Index (RCRI) (TABLE 1).⁷ Published in 1999, the RCRI was derived from a cohort of 2800 patients, verified in 1400 patients, and has been validated in numerous studies.² Each element increases the odds of a cardiac complication by a factor of 2 to 3, and more than one positive response indicates the patient is at high risk for complications.⁷

While a risk calculator remains your primary tool, elements such as smoking cessation and identifying sleep apnea are important parts of the equation.

The ACS NSQIP risk calculator has been criticized because it has not been validated in a group separate from the initial patient population used in its development.² Another criticism is the inclusion of the American Society of Anesthesiologists' (ASA) classification of the overall health of the patient, a simple yet subjective and unreliable method of patient characterization.²

Choosing a calculator. The ACS NSQIP calculator may be more useful for primary care physicians because it provides individualized risks for numerous complications and is easy to use. The output page can be printed as documentation of the preoperative evaluation, and is useful for counseling patients about reconsideration of surgery or risk-reduction strategies. The RCRI is also simple to use, but considers only cardiac risk. Although the RCRI has been validated in numerous studies, the ACS NSQIP was derived from a more substantial 1.4 million patients.

The next step in the preoperative evaluation process is to calculate your patient’s risk score and determine whether it is low or high. If the risk is determined to be low—either an RCRI score <2 or an ACS NSQIP cardiac complication risk <1%—the patient can be referred to surgery without further evaluation.²

If the patient has a functional status of >4 METs, refer him or her for surgery without further evaluation.

If the calculator suggests higher risk, the patient’s functional status should be assessed. If the patient has a functional status of >4 metabolic equivalents (METs), then the patient can be recommended for surgery without further evaluation.² Examples of activities that are greater than 4 METs are yard work such as raking leaves, weeding, or pushing a power mower; sexual relations; climbing a flight of stairs; walking up a hill; and participating in moderate recreational activities like golf, bowling, dancing, doubles tennis, or throwing a baseball or football.⁹

Patient can’t perform >4 METs? If the patient does not have a functional capacity of >4 METs, further risk stratification should be considered if the results would change management.² Prior guidelines recommended either perioperative beta-blockers to mitigate risk or coronary interventions, but both are controversial due to lack of proven benefit.

Perioperative beta-blocker use. A recommendation to consider starting beta-blockers at least one day prior to surgery remains in the 2014 ACC/AHA guidelines for patients with 3 or more RCRI risk factors.² But a group of studies supporting beta-blocker use has been discredited due to serious flaws and fabricated data. At the same time, a large study arguing against perioperative beta-blockers has been criticized for starting high doses of beta-blockers on the day of surgery.^2,10,11 In the end, mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.²

Stress testing is of questionable value. A patient with high cardiac risk (as evaluated with a calculator) may need to forego the surgical procedure or undergo a modified procedure. Alternatively, he or she may need to be referred to a cardiologist for consultation and possible pharmacologic nuclear stress testing. Although a normal stress test has a high negative predictive value, an abnormal test often leads to percutaneous coronary intervention or bypass surgery, and neither has been shown to reduce cardiac surgical risk.² Percutaneous coronary interventions require a period of dual antiplatelet therapy, delaying surgery for unproven benefit.²

EKGs and echocardiograms are of limited use. An anesthesia group or surgical center will often require an electrocardiogram (EKG) as part of a preoperative evaluation, but preoperative evaluation by EKG or echocardiogram is controversial due to unproven benefits and potential risks. The 2014 ACC/AHA guidelines recommend against a 12-lead EKG for patients with low cardiac risk using the RCRI or ACS NSQIP or those who are having a low-risk procedure, such as endoscopy or cataract surgery.² The United States Preventive Health Services Task Force also recommends against screening low-risk patients and says that screening EKGs and stress testing in asymptomatic medium- to high-risk patients is of undetermined value.¹² They noted no evidence of benefit from resting or exercise EKG, with harm from a 1.7% complication rate of angiography, which is performed after up to 2.9% of exercise EKG testing.¹²

Mortality benefit from perioperative beta-blockers is uncertain, and the suggested reduction in cardiac events is partially offset by an increased risk of stroke.

There are no recommendations for preoperative echocardiogram in the asymptomatic patient. Only unexplained dyspnea or other clinical signs of heart failure require an echocardiogram. For patients with known heart failure that is clinically stable, the ACC/AHA guidelines suggest that an echocardiogram should be performed within the year prior to surgery, although this is based on expert opinion.²

Because of the controversy over both coronary interventions and perioperative beta-blocker therapy, consider cardiology referral for a patient with poor functional activity level who does not meet low-risk criteria. While stress testing is acceptable, it may not lead to improved patient outcomes.

Optimize preventive care

Begin by ensuring that blood pressure (BP) and cholesterol are managed according to ACC/AHA guidelines. Then consider whether to start preoperative medications. You'll also want to screen for sleep apnea and discuss smoking status and cessation, if appropriate.

Initiate medications preoperatively?

In addition to having value as long-term primary prevention, there is some evidence that statins help prevent cardiac events during surgery. A randomized trial of over 200 vascular surgery patients showed that starting statins an average of 30 days prior to surgery significantly reduced cardiac complications.¹³ Another systematic review demonstrated that preoperative statins significantly reduce acute kidney injury from surgery.¹⁴

Unlike statins, aspirin started prior to surgery does not confer benefit. Aspirin was shown to significantly increase bleeding risk without improving cardiac outcomes in a large trial.¹⁵

Screen for sleep apnea

Sleep apnea increases the rate of respiratory failure between 2 and 3 times and the rate of cardiac complications about 1.5 times.¹⁶ This is a potentially correctable risk factor. The European Society of Anaesthesiology recommends clinical screening for obstructive sleep apnea using the STOP-Bang screening tool⁵ (TABLE 2⁴). For its part, the ASA combines screening questions from the STOP-Bang screening questionnaire with a review of the medical record and physical exam, because the STOP-Bang questionnaire alone has an insufficient negative predictive value, ranging from 30% and 82%.⁶ Obstructive sleep apnea is not addressed on published pulmonary and cardiac risk tools.^2,3,7,8

Is the patient a smoker?

Smoking is a reversible risk factor for pulmonary, cardiac, and infectious complications, as well as overall mortality. Perioperative smoking cessation counseling has been complicated by concerns that stopping smoking within 8 weeks of surgery might worsen postoperative outcomes. A study that looked at intraoperative sputum retrieved via tracheal suction showed that patients who had stopped smoking for 2 months or more prior to surgery had the same amount of sputum as non-smokers, while those that quit smoking <2 months before surgery were more likely to have increased intraoperative sputum volume.¹⁸ This study did not demonstrate a difference in postoperative pulmonary complications, likely because it included patients receiving minor surgeries only. But based on this study, a cessation period of 2 months was often recommended.

A recent systematic review showed that smoking cessation shortly before surgery does not increase risk.¹⁹ In fact, although the review did not show a statistically significant reduction in postoperative complications among recent quitters as compared with continued smokers, there was a trend toward a reduction in overall complications with only a slight increase in pulmonary complications.¹⁹

Address potential pulmonary complications

In addition to screening for issues that could lead to cardiac complications, it’s important to address the potential for pulmonary complications. Postoperative pulmonary complications are at least as common as cardiac complications, and include all possible respiratory related outcomes of surgery, from pneumonia to respiratory failure.

During the preoperative evaluation, verify that BP and cholesterol are managed per ACC/AHA guidelines.

The seminal study on postoperative pulmonary complications is a systematic review published in 2006, which showed that the most important risk factors were surgery type, advanced age, ASA classification of overall health ≥II, and congestive heart failure.³ Chronic lung diseases and cigarette use were less predictive of pulmonary issues. All of these factors are included in the ACS NSQIP risk calculator.

One aspect of the preoperative evaluation that should not be overlooked is a thorough medication reconciliation. Primary care providers can support the operative team by recommending medication adjustments prior to surgery. Several classes of medications have specific perioperative recommendations, which are summarized here.

Hypertension medications

• Beta-blockers. A patient who regularly takes a beta-blocker should continue the medication on the day of surgery and restart after surgery.^2,20
• Calcium channel blockers. Calcium channel blockers can be continued through the day of surgery.^2,20
• Renin-angiotensin system antagonists. Given the increased risk of hypotension following anesthesia induction, have patients refrain from taking angiotensin-converting enzyme inhibitors and angiotensin receptor blocker medications for at least 10 hours prior to surgery.²⁰
• Diuretics. Diuretics can be given on the day of surgery, although they increase the risk of hypovolemia and electrolyte disturbances.²⁰

Diabetes medications

• Insulin. For patients with type I diabetes, recommend basal insulin of 0.2 to 0.3 units/kg/day of long-acting insulin.²¹ If the patient is using an insulin pump, basal rate should be continued. For patients with type 2 diabetes, the simplest method is to use one-half the normal long-acting insulin dose on the morning of surgery.²²
• Metformin. Discontinue metformin 24 hours prior to surgery because of the risk for lactic acidosis.^21,22 While the risk of lactic acidosis from metformin is low, mortality rates as high as 50% have been documented after lactic acidosis occurred with similar medications.²²
• Sulfonylureas. Sulfonylureas should be held on the day of surgery due to the risk of hypoglycemia and a possible increased risk of ischemia.^21,22
• Thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 agonists. All should be held on the day of surgery.²¹

Anticoagulant medications

Whether patients quit smoking less than or more than 2 months before surgery is less important than that they quit.

• Vitamin K antagonists (warfarin). Discontinue warfarin 5 days prior to the procedure. The half-life is approximately 40 hours, requiring at least 5 days for the anticoagulant effect to be eliminated from the body.²³ Use of bridging therapy with regular- or low-molecular weight heparin remains controversial due to increased surgical bleeding risk without evidence of a decrease in cardiovascular events.²⁴ The patient’s risks of stroke and venous thromboembolism should be taken into account when deciding whether to use bridging therapy or not.
• Factor Xa inhibitor. Management of factor Xa inhibitors (rivaroxaban, apixaban) depends on the bleeding risk of the surgery and the patient’s renal function.^24,25 For instance, a patient undergoing cataract surgery (low risk) needs a shorter cessation time than a patient undergoing hip arthroplasty (high risk). Discontinuation times are listed in TABLE 3.²⁴
• Direct thrombin inhibitor. Management of direct thrombin inhibitors (dabigatran) is also dependent on surgical bleeding risk and renal function (TABLE 3).^23,24
• Aspirin, clopidogrel, ticlopidine, prasugrel. All should be stopped 7 to 10 days prior to surgery to allow new platelet growth. Low-dose aspirin for secondary prevention of cardiovascular disease or primary prevention in a high-risk patient can be continued through surgery.²³

Other

• Corticosteroids. Recent evidence suggests that stress-dose steroids are not needed to prevent adrenal insufficiency in patients taking corticosteroids chronically.²⁶ These patients should continue maintenance therapy at regular dosing.^26,27 Stress dosing of corticosteroids is only required when a patient has signs of adrenal insufficiency.²⁶
• Statins. Statin medications should be continued on the day of surgery.²
• Nonsteroidal anti-inflammatory drugs. NSAIDs should be stopped 5 days prior to surgery to reverse antiplatelet effects.²³

CORRESPONDENCE
CDR Michael J. Arnold, Naval Hospital, 2080 Child Street, Jacksonville, FL 32214; [email protected].

ACKNOWLEDGEMENT
The authors thank CDR Kristian Sanchack and LCDR Dustin Smith for their assistance with this manuscript.

Food and Drug Administration (FDA) Commissioner Robert Califf, MD, will deliver a keynote address on the opening morning of the NORD Rare Diseases and Orphan Products Breakthrough Summit to take place Oct. 17 and 18 in Arlington Virginia. Approximately one-third of the novel new drugs approved by FDA in recent years have been “orphan” drugs for rare diseases.

Dr. Califf will be joined on the program agenda by more than 25 additional FDA speakers, including Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research, and Peter Marks, MD, PhD, Director of FDA’s Center for Biologics Evaluation and Research.

On Day Two of the conference, Kate Rawson, Senior Editor at Prevision Policy, will provide the morning keynote with a look ahead at possible implications of the national election for the rare disease community.  The NORD Summit attracts medical professionals, patient advocates, and others to examine issues related to rare disease research, diagnosis, treatment, and patient access to care. The conference is open to all. Click here to view the agenda.

Food and Drug Administration (FDA) Commissioner Robert Califf, MD, will deliver a keynote address on the opening morning of the NORD Rare Diseases and Orphan Products Breakthrough Summit to take place Oct. 17 and 18 in Arlington Virginia. Approximately one-third of the novel new drugs approved by FDA in recent years have been “orphan” drugs for rare diseases.

Dr. Califf will be joined on the program agenda by more than 25 additional FDA speakers, including Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research, and Peter Marks, MD, PhD, Director of FDA’s Center for Biologics Evaluation and Research.

On Day Two of the conference, Kate Rawson, Senior Editor at Prevision Policy, will provide the morning keynote with a look ahead at possible implications of the national election for the rare disease community.  The NORD Summit attracts medical professionals, patient advocates, and others to examine issues related to rare disease research, diagnosis, treatment, and patient access to care. The conference is open to all. Click here to view the agenda.

Food and Drug Administration (FDA) Commissioner Robert Califf, MD, will deliver a keynote address on the opening morning of the NORD Rare Diseases and Orphan Products Breakthrough Summit to take place Oct. 17 and 18 in Arlington Virginia. Approximately one-third of the novel new drugs approved by FDA in recent years have been “orphan” drugs for rare diseases.

Dr. Califf will be joined on the program agenda by more than 25 additional FDA speakers, including Janet Woodcock, MD, Director of FDA’s Center for Drug Evaluation and Research, and Peter Marks, MD, PhD, Director of FDA’s Center for Biologics Evaluation and Research.

On Day Two of the conference, Kate Rawson, Senior Editor at Prevision Policy, will provide the morning keynote with a look ahead at possible implications of the national election for the rare disease community.  The NORD Summit attracts medical professionals, patient advocates, and others to examine issues related to rare disease research, diagnosis, treatment, and patient access to care. The conference is open to all. Click here to view the agenda.

Although vitamin and mineral deficiencies are relatively uncommon in the United States and other developed countries, physicians must be alert to them, particularly in specific populations such as infants, pregnant women, alcoholics, vegetarians, people of lower socioeconomic status, and patients on dialysis, on certain medications, or with a history of malabsorption or gastrointestinal surgery. The skin is commonly affected by nutritional deficiencies and can provide important diagnostic clues.

This article reviews the consequences of deficiencies of zinc and vitamins A, B₂, B₃, B₆, and C, emphasizing dermatologic findings.

ZINC DEFICIENCY

Case: A colon cancer patient on total parenteral nutrition

A 65-year-old woman who had been on total parenteral nutrition for 4 months after undergoing surgical debulking for metastatic colon cancer was admitted for evaluation of a rash on her face and extremities and failure to thrive. The rash had started 10 days earlier as small red papules and vesicles on the forehead and progressed to cover the forehead and lips. She had been prescribed prednisone 20 mg daily, but the condition had not improved.

Physical examination revealed numerous violaceous papules, plaques, and vesicles on her face, legs, and feet (Figure 1). The vesicles were tender to touch and some were crusted. Biopsy of a lesion on her leg revealed psoriasiform dermatitis with prominent epidermal pallor and necrosis (Figure 2), suggestive of a nutritional deficiency.

Blood testing revealed low levels of alkaline phosphatase and zinc. She was started on zinc supplementation (3 mg/kg/day), and her cutaneous lesions improved within a month, confirming the diagnosis of zinc deficiency.

Zinc is an essential trace element

Zinc is an essential trace element required for function of many metalloproteases and transcription factors involved in reproduction, immunology, and wound repair. Additionally, its antioxidant properties help prevent ultraviolet radiation damage.¹

The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women, with higher amounts for pregnant and lactating women.¹ The human body does not store zinc, and meat and eggs are the most important dietary sources.¹

The normal plasma zinc level is 70 to 250 µL/dL, and hypozincemia can be diagnosed with a blood test. For the test to be accurate, zinc-free tubes should be used, anticoagulants should be avoided, the blood should not come into contact with rubber stoppers, and blood should be drawn in the morning due to diurnal variation in zinc levels. Additionally, zinc levels may be transiently low secondary to infection. Thus, the clinical picture, along with zinc levels, histopathology, and clinical response to zinc supplementation are necessary for the diagnosis of zinc deficiency.²

Since zinc is required for the activity of alkaline phosphatase (a metalloenzyme), serum levels of alkaline phosphatase correlate with zinc levels and can be used as a serologic marker for zinc levels.³

Zinc deficiency is a worldwide problem, with a higher prevalence in developing countries. It can result from either inadequate diet or impaired absorption, which can be acquired or inherited.

Clinical forms of zinc deficiency

Acrodermatitis enteropathica, an inherited form of zinc deficiency, is due to a mutation in the SLC39A4 gene encoding a zinc uptake protein.⁴ Patients typically present during infancy a few weeks after being weaned from breast milk. Clinical presentations include diarrhea, periorificial (eg, around the mouth) and acral dermatitis, and alopecia, although only 20% of patients have all these findings at presentation.⁵ Occasionally, diaper rash, photosensitivity, nail dystrophy, angular stomatitis, conjunctivitis, blepharitis, and growth retardation are observed. Serum levels of zinc and alkaline phosphatase are low.⁵ Clinical and serologic markers improve within 2 to 3 weeks with oral zinc supplementation (2–3 mg/kg/day).

Acquired forms of zinc deficiency are linked to poor socioeconomic status, diet, infections, renal failure, pancreatic insufficiency, cystic fibrosis, and malabsorption syndromes.^1,6,7 Cutaneous findings in acquired cases of zinc deficiency are similar to those seen in acrodermatitis enteropathica. Periorificial lesions are a hallmark of this condition, and angular cheilitis is an early manifestation. Eczematous annular plaques typically develop in areas subjected to repeated friction and pressure and may evolve into vesicles, pustules, and bullae.² On biopsy study, lesions are characterized by cytoplasmic pallor, vacuolization, and necrosis of keratinocytes, which are common findings in nutritional deficiencies.⁸ Dystrophic nails, structural hair changes, and diminished growth of both hair and nails have been reported.²

Cutaneous lesions due to hypozincemia respond quickly to zinc supplementation (1–3 mg/kg/day), usually without permanent damage.² However, areas of hypo- and hyperpigmentation may persist.

VITAMIN C DEFICIENCY

Case: A lung transplant recipient on peritoneal dialysis

A 59-year-old bilateral lung transplant patient with a history of chronic kidney disease on peritoneal dialysis for the past 2 years was admitted for peritonitis. He had developed tender violaceous papules and nodules coalescing into large plaques on his arms and perifollicular purpuric macules on both legs 3 days before admission (Figure 3). The lesions were painful to the touch, and some bled at times. Tender gums, bilateral edema, and corkscrew hair were also noted (corkscrew hair is shown in another patient in Figure 4).

Biopsy of a lesion on the forearm was consistent with lymphangiectasia secondary to edema. Staining for bacteria and fungi was negative.

Serologic investigation revealed low vitamin C serum levels (7 µmol/L, reference range 23–114 µmol/L). Supplementation with 1 g/day of vitamin C was started and resulted in gradual improvement of the purpura. The patient died 4 months later of complications of comorbidities.

An important antioxidant

Vitamin C, or ascorbic acid, is an important antioxidant involved in the synthesis of tyrosine, tryptophan, and folic acid and in the hydroxylation of glycine and proline, a required step in the formation of collagen.⁹ Humans cannot synthesize vitamin C and must acquire it in the diet.⁹ Plants are the most important dietary sources.⁹ Although vitamin C is generally not toxic and its metabolites are renally cleared, diarrhea and other gastrointestinal disturbances can occur if large amounts are ingested.¹⁰

Vitamin C deficiency is rare in developed countries and is linked to malnutrition. Risk factors include alcoholism, severe psychiatric illness, anorexia, and low socioeconomic status. Moreover, multiple conditions including stress, viral illness, smoking, fever, and use of antibiotics lead to diminished vitamin C bioavailability.⁹ Patients on dialysis are at increased risk of vitamin C deficiency since it is lost during the process.¹¹

The RDA for vitamin C is 90 mg for men and 75 mg for women, with higher requirements during pregnancy and lactation.¹² This is much higher than the amount needed to prevent scurvy, 10 mg/day.¹³

Scurvy is the classic manifestation

The classic manifestations of vitamin C deficiency are scurvy and Barlow disease, also known as infantile scurvy.

Early manifestations of vitamin C deficiency such as fatigue, mood changes, and depression appear after 1 to 3 months of inadequate intake.¹³ Other manifestations are anemia, bone pain, hemorrhage into joints, abnormal vision, and possibly osteoporosis.

Cutaneous findings are a hallmark of scurvy. Follicular hyperkeratosis with fragmented corkscrew hair and perifollicular hemorrhages on posterior thighs, forearms, and abdomen are pathognomonic findings that occur early in the disease.¹³ The cutaneous hemorrhages can become palpable, particularly in the lower limbs. Diffuse petechiae are a later finding along with ecchymosis, particularly in pressure sites such as the buttocks.¹³ “Woody edema” of the legs with ecchymosis, pain, and limited motion can also arise.¹⁴ Nail findings including koilonychia and splinter hemorrhages are common.^13,14

Vitamin C deficiency results in poor wound healing with consequent ulcer formation due to impaired collagen synthesis. Hair abnormalities including corkscrew and swan-neck hairs are common in scurvy due to vitamin C’s role in disulfide bond formation, which is necessary for hair synthesis.¹³

Scurvy also affects the oral cavity: gums typically appear red, swollen, and shiny earlier in the disease and can become black and necrotic later.¹³ Loosening and loss of teeth is also common.¹³

Scurvy responds quickly to vitamin C supplementation. Patients with scurvy should receive 1 to 2 g of vitamin C daily for 2 to 3 days, 500 mg daily for the next week, and 100 mg daily for the next 1 to 3 months.¹⁵ Fatigue, pain, and confusion usually improve in the first 24 hours of treatment, cutaneous manifestations respond in 2 weeks, and hair within 1 month. Complete recovery is expected within 3 months on vitamin C supplementation.¹⁵

VITAMIN A DEFICIENCY

Case: A girl with short-bowel syndrome on total parenteral nutrition

A 14-year-old girl who had been on total parenteral nutrition for the past 3 years due to short-bowel syndrome was admitted for evaluation for a second small-bowel transplant. She complained of dry skin and dry eyes. She was found to have rough, toad-like skin with prominent brown perifollicular hyperkeratotic papules on buttocks and extremities (Figure 5). Additionally, corkscrew hairs were noted. Physical examination was consistent with phrynoderma.

Blood work revealed low levels of vitamin A (8 µg/dL, reference range 20–120 µg/dL) and vitamin C (20 µmol/L, reference range 23–114 µmol/L). After bowel transplant, her vitamin A levels normalized within 2 weeks and her skin improved without vitamin A supplementation.

Essential for protein synthesis

Vitamin A is a group of fat-soluble isoprenoids that includes retinol, retinoic acid, and beta-carotene. It is stored in hepatic stellate cells, which can release it in circulation for distribution to peripheral organs when needed.¹⁶

Vitamin A is essential for protein synthesis in the eye and is a crucial component of phototransduction.¹⁷ It is also an important modulator of the immune system, as it enhances cytotoxicity and proliferation of T cells while suppressing B-cell proliferation.¹⁸ Additionally, vitamin A plays an important role in the skin, where it promotes cell mitosis and increases epithelial thickness, the number of Langerhans cells, and glycosaminoglycan synthesis.^19–21

Deficiency associated with malabsorption, liver disease, small-bowel surgery

Vitamin A deficiency is rare in developed countries overall, but it is associated with malabsorption, liver disease, and small-bowel surgery.²² Indeed, 4 years after undergoing bariatric surgery, 69% of patients in one series had deficiencies in vitamin A and other fat-soluble vitamins.²³ The typical manifestations are nyctalopia (night blindness) and xerophthalmia (inability to produce tears).

Phrynoderma, or “toad skin,” is a cutaneous manifestation of vitamin A deficiency. The association between phrynoderma and vitamin A deficiency was established in 1933 when prisoners in Africa with nyctalopia, xerophthalmia, and phrynoderma showed improvement in all three conditions when treated with cod oil, which is rich in vitamin A.²⁴

Phrynoderma is characterized by dry, hyperkeratotic papules with central intrafollicular plugs projecting from hair follicles.²⁵ The lesions are typically symmetrically distributed on the face, the skull, and the extensor surfaces of the shoulders, buttocks, and extremities, but they can extend to the entire body in severe cases.²⁵ They typically get better with improved nutrition.

Evidence is mounting to suggest phrynoderma is a cutaneous manifestation of diverse nutritional deficiencies, not just vitamin A. For example, some children with phrynoderma have normal levels of vitamin A,²⁶ and a trial showed that patients with phrynoderma benefited from intramuscular injections of either vitamin A or vitamin B complex, particularly when also treated with topical keratolytics.²⁷ Thus, patients who present with the typical lesions of phrynoderma should be screened for nutritional deficiencies beyond vitamin A.

VITAMIN B₆ DEFICIENCY

Case: A woman with sepsis

A 62-year-old woman with a 4-year history of unspecified dermatitis, intertriginous rashes, and skin ulcerations with polymicrobial infections was admitted for sepsis. She reported that her rash had worsened over the previous 2 weeks. Physical examination revealed generalized xerosis, an inflamed bright red tongue with atrophy of distal papillae, and red painful erosions in intertriginous areas (Figure 6).

Blood testing revealed low levels of vitamin B₂ (< 5.0 nmol/L, reference range 6.2–39 nmol/L) and vitamin B₆ (3.1 nmol/L, reference range 20–125 nmol/L). She was started on supplementation with vitamin B₆ 50 mg/day and vitamin B₂ 200 mg/day, and her dermatitis and ulcers improved.

Pyridoxine and its derivatives

Pyridoxine and its derivatives are collectively known as vitamin B₆. Vitamin B₆ can be stored throughout the body, particularly in muscle and the liver, whereas its oxidized version is excreted mostly in the urine.^28,29 Vitamin B₆ serves as a cofactor to more than 140 enzymes, it is required for tryptophan metabolism and synthesis of nicotinic acid, and it is a cofactor for alanine aminotransferase and aspartate aminotransferase.^28,29

Vitamin B₆ deficiency is rare in the general population. The median daily intake is 2 mg/day for men and 1.5 mg/day for women, whereas the RDA for adults is 1.3 mg/day. No signs of vitamin B₆ deficiency have been noted at intakes greater than 0.5 mg/day in clinical studies.²⁸

However, chronic alcoholism poses a high risk of this deficiency because it decreases the intake of vitamin B₆ and decreases the ability of the liver to store it. Additionally, patients with eclampsia or preeclampsia or who are on dialysis have higher vitamin B₆ requirements.²⁸ Certain medications are also associated with a low vitamin B₆ level, in particular the antituberculosis medication isoniazid, penicillamine, and hydralazine.²⁸

Although clinical manifestations of vitamin B₆ deficiency are rare, subclinical deficiency may be common, particularly in the elderly,²⁸ as up to 23% of people ages 65 to 75 and 40% of those older than 85 have vitamin B₆ deficiency.^30,31

Features of vitamin B₆ deficiency

Vitamin B₆ deficiency is associated with anemia (hypochromic, microcytic, iron-refractory), impaired immune function, seizures, peripheral neuropathy, and glossitis. Experimentally induced deficiency of vitamin B₆ results in periorificial dermatitis within 3 weeks.³² Intriguingly, multiple studies have shown an inverse correlation between B₆ levels and diverse cancers, including colorectal, pancreatic, and lung cancer.²⁸

Given its role in the synthesis of nicotinic acid, vitamin B₆ deficiency results in abnormal levels of B₃. Thus, vitamin B₆ deficiency may result in a pellagra-like presentation (reviewed in detail below in the discussion of vitamin B₃ deficiency). In this case, giving vitamin B₃ does not result in significant improvement, and this failure helps to establish the diagnosis of vitamin B₆ deficiency.³² It is believed that pellagrous lesions in vitamin B₆ deficiency are due to decreased synthesis of proline from ornithine, as suggested by decreased levels of the enzyme ornithine aminotransferase in patients with low vitamin B₆.³³ Other cutaneous manifestations of vitamin B₆ deficiency include eczema and seborrheic dermatitis.³³

Vitamin B₆ can be measured in blood and urine. Although these levels only reflect recent intake, plasma values lower than 20 nmol/L are indicative of vitamin B₆ deficiency.³⁴ Therapeutic oral supplementation of vitamin B₆ is the treatment of choice. Vitamin B₆ treatment is safe, but exposure to high levels of vitamin B₆ may result in photosensitivity and dermatitis.³⁵

Vitamin B₂ (riboflavin) deficiency

Riboflavin, or vitamin B₂, is a water-soluble vitamin involved in diverse reduction-oxidation reactions. Its active forms—flavin adenine dinucleotide and flavin mononucleotide—act as electron carriers in the respiratory electron transfer chain, and the former is necessary for the oxidation of fatty acids.³⁶ The human body does not store riboflavin, and excess intake is excreted in the urine.³⁶

Milk, dairy products, and meat are the major dietary sources of vitamin B₂. Additionally, some colonic bacteria synthesize it and provide an additional source.³⁶ Patients whose diets are low in dairy and meat products, in particular vegetarians, alcoholics, and the elderly, are at risk of this deficiency. Other populations at risk are pregnant women, lactating women, premature infants, infants exposed to phototherapy for hyperbilirubinemia, and infants of mothers with low vitamin B₂ levels.^36,37

The RDA for vitamin B₂ is 1.3 mg/day for men and 1.1 mg/day per women, with higher requirements for pregnant and lactating women. Fortunately, the median intake of riboflavin from diet in the United States is 2 mg/day for men and 1.5 mg/day for women.³⁸

Features of vitamin B₂ deficiency

Features of vitamin B₂ deficiency include angular stomatitis, glossitis, cheilosis, nasolabial dermatitis, and rarely corneal vascularization.^39,40 Dermatitic lesions around the scrotum and labia are common and are in many cases the initial manifestation of vitamin B₂ deficiency.^39,40 Riboflavin deficiency during development results in muscular, skeletal, and gastrointestinal abnormalities. In adults, riboflavin deficiency is associated with anemia, decreased iron absorption, neurodegeneration, and peripheral neuropathy.³⁶

Vitamin B₂ deficiency usually coexists with other deficiencies, and riboflavin is involved in the metabolism of other B vitamins including B₃, B₆, B₉ (folate), and B₁₂. Thus, the clinical presentation of vitamin B₂ deficiency is similar to that of vitamin B₃ and B₆ deficiency (reviewed above and below) and has been described as pellagra sine pellagra (pellagra without pellagra). Moreover, correction of riboflavin deficiency results in increased levels of vitamin B₃ and B₆.³⁶

Vitamin B₂ levels can be measured in the urine and blood.³⁷ Oral supplementation is safe (up to 60 mg/day) and is the treatment of choice.^36,38 Clearance of lesions within 3 to 5 days of riboflavin supplementation confirms the diagnosis.⁴⁰

Vitamin B₃ (niacin) deficiency

Niacin, or vitamin B₃, is a water-soluble vitamin abundant in meat, eggs, and legumes. It is an essential cofactor for coenzyme I and coenzyme II; therefore, it plays a crucial role in ATP synthesis, glycolysis, and metabolism of fatty acids and amino acids.^41,42

Most niacin is acquired in the diet, but humans can synthesize it from tryptophan in the presence of vitamin B₆ and thiamine.⁴² Thus, a deficiency in tryptophan, vitamin B₆, or thiamine can also lead to low niacin, and  an excess of dietary leucine can interfere with niacin synthesis and result in deficiency.⁴²

The RDA for niacin is 6 to 20 mg/day, based on sex and age, with higher requirements for pregnant and lactating women.³⁸

Pellagra, the clinical manifestation

Pellagra is the clinical manifestation of niacin deficiency, although it is thought that lack of tryptophan, vitamin B₆, or thiamine may also be required for clinical symptoms to appear.⁴¹

Sporadic cases of pellagra occur in homeless people, alcoholics, drug abusers, people with anorexia, and food faddists.^41,42 Symptoms typically develop after about 50 days of a niacin-free diet.⁴¹ Pellagra may also develop due to impaired absorption or metabolism, particularly in patients with prolonged diarrhea, colitis, ileitis, hepatic cirrhosis, or Hartnup disease.^42–45 Certain medications, eg, isoniazid, 5-fluorouracil, azathioprine, and 6-mercaptopurine, interfere with niacin synthesis and may induce pellagra in susceptible patients.⁴²

The clinical course of pellagra is often described by the four “Ds”: dermatitis, dementia, diarrhea, and, when not corrected, death. Early symptoms of insufficient vitamin B₃ are weakness, fatigue, loss of appetite, depression, and mood changes.⁴²

The cutaneous manifestations of pellagra are impressive and include photosensitive eruptions, perineal lesions, and thickened and pigmented skin.⁴¹ Biopsy of affected and unaffected skin in pellagra patients shows abnormal keratinization.

Photosensitivity is an initial manifestation of pellagra.⁴⁶ It is believed that vitamin B₃ deficiency results in a lack of urocanic acid, a compound that protects against ultraviolet B damage and accumulation of kynurenic acid, a known phototoxic agent.⁴⁷

The initial stage of acute pellagra can resemble a sunburn on the face, neck, and dorsal extremities⁴⁷ that becomes darker with time instead of fading.⁴⁶ Sharply demarcated hyperpigmented areas on the arms and legs are known as the “glove” and “boot” of pellagra.⁴⁶ Nearly all patients have involvement of the dorsum of the hand.⁴² The Casal necklace may be present, a characteristic eruption observed in up to 76% of patients on the front of the neck in the region of C3-C4.⁴⁸

As the disease progresses, lesions harden and become brittle—hence, the name pellagra, which means “rough skin.” Perineal lesions are also common, along with fissures and ulcerations. Additionally, about a third of pellagra patients have involvement of the lips, tongue, and oral mucosa.⁴² Notably, patients with drug-induced or Hartnup-related pellagra do not develop genital, perineal, oral, or hyperkeratotic lesions.⁴⁶

Although untreated pellagra can lead to death in 5 years,⁴² the disease responds dramatically to oral nicotinamide (250–500 mg/day), which is preferred over niacin due to the latter’s vasomotor effects.⁴¹ Therapy also includes caloric supplementation, other B vitamins, zinc, and magnesium.⁴²

NUTRITIONAL DEFICIENCIES TEND TO COEXIST

The clinical scenarios presented here emphasize how different nutritional deficiencies can manifest with overlapping features. But nutritional deficiencies, particularly those associated with underlying conditions, tend to coexist rather than occur in isolation.

Although associated with significant morbidity, nutritional deficiencies can be easily addressed, particularly when promptly identified. Careful evaluation of the history and clinical and serologic findings is necessary to correctly diagnose and address these conditions.

Although vitamin and mineral deficiencies are relatively uncommon in the United States and other developed countries, physicians must be alert to them, particularly in specific populations such as infants, pregnant women, alcoholics, vegetarians, people of lower socioeconomic status, and patients on dialysis, on certain medications, or with a history of malabsorption or gastrointestinal surgery. The skin is commonly affected by nutritional deficiencies and can provide important diagnostic clues.

This article reviews the consequences of deficiencies of zinc and vitamins A, B₂, B₃, B₆, and C, emphasizing dermatologic findings.

ZINC DEFICIENCY

Case: A colon cancer patient on total parenteral nutrition

A 65-year-old woman who had been on total parenteral nutrition for 4 months after undergoing surgical debulking for metastatic colon cancer was admitted for evaluation of a rash on her face and extremities and failure to thrive. The rash had started 10 days earlier as small red papules and vesicles on the forehead and progressed to cover the forehead and lips. She had been prescribed prednisone 20 mg daily, but the condition had not improved.

Physical examination revealed numerous violaceous papules, plaques, and vesicles on her face, legs, and feet (Figure 1). The vesicles were tender to touch and some were crusted. Biopsy of a lesion on her leg revealed psoriasiform dermatitis with prominent epidermal pallor and necrosis (Figure 2), suggestive of a nutritional deficiency.

Blood testing revealed low levels of alkaline phosphatase and zinc. She was started on zinc supplementation (3 mg/kg/day), and her cutaneous lesions improved within a month, confirming the diagnosis of zinc deficiency.

Zinc is an essential trace element

Zinc is an essential trace element required for function of many metalloproteases and transcription factors involved in reproduction, immunology, and wound repair. Additionally, its antioxidant properties help prevent ultraviolet radiation damage.¹

The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women, with higher amounts for pregnant and lactating women.¹ The human body does not store zinc, and meat and eggs are the most important dietary sources.¹

The normal plasma zinc level is 70 to 250 µL/dL, and hypozincemia can be diagnosed with a blood test. For the test to be accurate, zinc-free tubes should be used, anticoagulants should be avoided, the blood should not come into contact with rubber stoppers, and blood should be drawn in the morning due to diurnal variation in zinc levels. Additionally, zinc levels may be transiently low secondary to infection. Thus, the clinical picture, along with zinc levels, histopathology, and clinical response to zinc supplementation are necessary for the diagnosis of zinc deficiency.²

Since zinc is required for the activity of alkaline phosphatase (a metalloenzyme), serum levels of alkaline phosphatase correlate with zinc levels and can be used as a serologic marker for zinc levels.³

Zinc deficiency is a worldwide problem, with a higher prevalence in developing countries. It can result from either inadequate diet or impaired absorption, which can be acquired or inherited.

Clinical forms of zinc deficiency

Acrodermatitis enteropathica, an inherited form of zinc deficiency, is due to a mutation in the SLC39A4 gene encoding a zinc uptake protein.⁴ Patients typically present during infancy a few weeks after being weaned from breast milk. Clinical presentations include diarrhea, periorificial (eg, around the mouth) and acral dermatitis, and alopecia, although only 20% of patients have all these findings at presentation.⁵ Occasionally, diaper rash, photosensitivity, nail dystrophy, angular stomatitis, conjunctivitis, blepharitis, and growth retardation are observed. Serum levels of zinc and alkaline phosphatase are low.⁵ Clinical and serologic markers improve within 2 to 3 weeks with oral zinc supplementation (2–3 mg/kg/day).

Acquired forms of zinc deficiency are linked to poor socioeconomic status, diet, infections, renal failure, pancreatic insufficiency, cystic fibrosis, and malabsorption syndromes.^1,6,7 Cutaneous findings in acquired cases of zinc deficiency are similar to those seen in acrodermatitis enteropathica. Periorificial lesions are a hallmark of this condition, and angular cheilitis is an early manifestation. Eczematous annular plaques typically develop in areas subjected to repeated friction and pressure and may evolve into vesicles, pustules, and bullae.² On biopsy study, lesions are characterized by cytoplasmic pallor, vacuolization, and necrosis of keratinocytes, which are common findings in nutritional deficiencies.⁸ Dystrophic nails, structural hair changes, and diminished growth of both hair and nails have been reported.²

Cutaneous lesions due to hypozincemia respond quickly to zinc supplementation (1–3 mg/kg/day), usually without permanent damage.² However, areas of hypo- and hyperpigmentation may persist.

VITAMIN C DEFICIENCY

Case: A lung transplant recipient on peritoneal dialysis

A 59-year-old bilateral lung transplant patient with a history of chronic kidney disease on peritoneal dialysis for the past 2 years was admitted for peritonitis. He had developed tender violaceous papules and nodules coalescing into large plaques on his arms and perifollicular purpuric macules on both legs 3 days before admission (Figure 3). The lesions were painful to the touch, and some bled at times. Tender gums, bilateral edema, and corkscrew hair were also noted (corkscrew hair is shown in another patient in Figure 4).

Biopsy of a lesion on the forearm was consistent with lymphangiectasia secondary to edema. Staining for bacteria and fungi was negative.

Serologic investigation revealed low vitamin C serum levels (7 µmol/L, reference range 23–114 µmol/L). Supplementation with 1 g/day of vitamin C was started and resulted in gradual improvement of the purpura. The patient died 4 months later of complications of comorbidities.

An important antioxidant

Vitamin C, or ascorbic acid, is an important antioxidant involved in the synthesis of tyrosine, tryptophan, and folic acid and in the hydroxylation of glycine and proline, a required step in the formation of collagen.⁹ Humans cannot synthesize vitamin C and must acquire it in the diet.⁹ Plants are the most important dietary sources.⁹ Although vitamin C is generally not toxic and its metabolites are renally cleared, diarrhea and other gastrointestinal disturbances can occur if large amounts are ingested.¹⁰

Vitamin C deficiency is rare in developed countries and is linked to malnutrition. Risk factors include alcoholism, severe psychiatric illness, anorexia, and low socioeconomic status. Moreover, multiple conditions including stress, viral illness, smoking, fever, and use of antibiotics lead to diminished vitamin C bioavailability.⁹ Patients on dialysis are at increased risk of vitamin C deficiency since it is lost during the process.¹¹

The RDA for vitamin C is 90 mg for men and 75 mg for women, with higher requirements during pregnancy and lactation.¹² This is much higher than the amount needed to prevent scurvy, 10 mg/day.¹³

Scurvy is the classic manifestation

The classic manifestations of vitamin C deficiency are scurvy and Barlow disease, also known as infantile scurvy.

Early manifestations of vitamin C deficiency such as fatigue, mood changes, and depression appear after 1 to 3 months of inadequate intake.¹³ Other manifestations are anemia, bone pain, hemorrhage into joints, abnormal vision, and possibly osteoporosis.

Cutaneous findings are a hallmark of scurvy. Follicular hyperkeratosis with fragmented corkscrew hair and perifollicular hemorrhages on posterior thighs, forearms, and abdomen are pathognomonic findings that occur early in the disease.¹³ The cutaneous hemorrhages can become palpable, particularly in the lower limbs. Diffuse petechiae are a later finding along with ecchymosis, particularly in pressure sites such as the buttocks.¹³ “Woody edema” of the legs with ecchymosis, pain, and limited motion can also arise.¹⁴ Nail findings including koilonychia and splinter hemorrhages are common.^13,14

Vitamin C deficiency results in poor wound healing with consequent ulcer formation due to impaired collagen synthesis. Hair abnormalities including corkscrew and swan-neck hairs are common in scurvy due to vitamin C’s role in disulfide bond formation, which is necessary for hair synthesis.¹³

Scurvy also affects the oral cavity: gums typically appear red, swollen, and shiny earlier in the disease and can become black and necrotic later.¹³ Loosening and loss of teeth is also common.¹³

Scurvy responds quickly to vitamin C supplementation. Patients with scurvy should receive 1 to 2 g of vitamin C daily for 2 to 3 days, 500 mg daily for the next week, and 100 mg daily for the next 1 to 3 months.¹⁵ Fatigue, pain, and confusion usually improve in the first 24 hours of treatment, cutaneous manifestations respond in 2 weeks, and hair within 1 month. Complete recovery is expected within 3 months on vitamin C supplementation.¹⁵

VITAMIN A DEFICIENCY

Case: A girl with short-bowel syndrome on total parenteral nutrition

A 14-year-old girl who had been on total parenteral nutrition for the past 3 years due to short-bowel syndrome was admitted for evaluation for a second small-bowel transplant. She complained of dry skin and dry eyes. She was found to have rough, toad-like skin with prominent brown perifollicular hyperkeratotic papules on buttocks and extremities (Figure 5). Additionally, corkscrew hairs were noted. Physical examination was consistent with phrynoderma.

Blood work revealed low levels of vitamin A (8 µg/dL, reference range 20–120 µg/dL) and vitamin C (20 µmol/L, reference range 23–114 µmol/L). After bowel transplant, her vitamin A levels normalized within 2 weeks and her skin improved without vitamin A supplementation.

Essential for protein synthesis

Vitamin A is a group of fat-soluble isoprenoids that includes retinol, retinoic acid, and beta-carotene. It is stored in hepatic stellate cells, which can release it in circulation for distribution to peripheral organs when needed.¹⁶

Vitamin A is essential for protein synthesis in the eye and is a crucial component of phototransduction.¹⁷ It is also an important modulator of the immune system, as it enhances cytotoxicity and proliferation of T cells while suppressing B-cell proliferation.¹⁸ Additionally, vitamin A plays an important role in the skin, where it promotes cell mitosis and increases epithelial thickness, the number of Langerhans cells, and glycosaminoglycan synthesis.^19–21

Deficiency associated with malabsorption, liver disease, small-bowel surgery

Vitamin A deficiency is rare in developed countries overall, but it is associated with malabsorption, liver disease, and small-bowel surgery.²² Indeed, 4 years after undergoing bariatric surgery, 69% of patients in one series had deficiencies in vitamin A and other fat-soluble vitamins.²³ The typical manifestations are nyctalopia (night blindness) and xerophthalmia (inability to produce tears).

Phrynoderma, or “toad skin,” is a cutaneous manifestation of vitamin A deficiency. The association between phrynoderma and vitamin A deficiency was established in 1933 when prisoners in Africa with nyctalopia, xerophthalmia, and phrynoderma showed improvement in all three conditions when treated with cod oil, which is rich in vitamin A.²⁴

Phrynoderma is characterized by dry, hyperkeratotic papules with central intrafollicular plugs projecting from hair follicles.²⁵ The lesions are typically symmetrically distributed on the face, the skull, and the extensor surfaces of the shoulders, buttocks, and extremities, but they can extend to the entire body in severe cases.²⁵ They typically get better with improved nutrition.

Evidence is mounting to suggest phrynoderma is a cutaneous manifestation of diverse nutritional deficiencies, not just vitamin A. For example, some children with phrynoderma have normal levels of vitamin A,²⁶ and a trial showed that patients with phrynoderma benefited from intramuscular injections of either vitamin A or vitamin B complex, particularly when also treated with topical keratolytics.²⁷ Thus, patients who present with the typical lesions of phrynoderma should be screened for nutritional deficiencies beyond vitamin A.

VITAMIN B₆ DEFICIENCY

Case: A woman with sepsis

A 62-year-old woman with a 4-year history of unspecified dermatitis, intertriginous rashes, and skin ulcerations with polymicrobial infections was admitted for sepsis. She reported that her rash had worsened over the previous 2 weeks. Physical examination revealed generalized xerosis, an inflamed bright red tongue with atrophy of distal papillae, and red painful erosions in intertriginous areas (Figure 6).

Blood testing revealed low levels of vitamin B₂ (< 5.0 nmol/L, reference range 6.2–39 nmol/L) and vitamin B₆ (3.1 nmol/L, reference range 20–125 nmol/L). She was started on supplementation with vitamin B₆ 50 mg/day and vitamin B₂ 200 mg/day, and her dermatitis and ulcers improved.

Pyridoxine and its derivatives

Pyridoxine and its derivatives are collectively known as vitamin B₆. Vitamin B₆ can be stored throughout the body, particularly in muscle and the liver, whereas its oxidized version is excreted mostly in the urine.^28,29 Vitamin B₆ serves as a cofactor to more than 140 enzymes, it is required for tryptophan metabolism and synthesis of nicotinic acid, and it is a cofactor for alanine aminotransferase and aspartate aminotransferase.^28,29

Vitamin B₆ deficiency is rare in the general population. The median daily intake is 2 mg/day for men and 1.5 mg/day for women, whereas the RDA for adults is 1.3 mg/day. No signs of vitamin B₆ deficiency have been noted at intakes greater than 0.5 mg/day in clinical studies.²⁸

However, chronic alcoholism poses a high risk of this deficiency because it decreases the intake of vitamin B₆ and decreases the ability of the liver to store it. Additionally, patients with eclampsia or preeclampsia or who are on dialysis have higher vitamin B₆ requirements.²⁸ Certain medications are also associated with a low vitamin B₆ level, in particular the antituberculosis medication isoniazid, penicillamine, and hydralazine.²⁸

Although clinical manifestations of vitamin B₆ deficiency are rare, subclinical deficiency may be common, particularly in the elderly,²⁸ as up to 23% of people ages 65 to 75 and 40% of those older than 85 have vitamin B₆ deficiency.^30,31

Features of vitamin B₆ deficiency

Vitamin B₆ deficiency is associated with anemia (hypochromic, microcytic, iron-refractory), impaired immune function, seizures, peripheral neuropathy, and glossitis. Experimentally induced deficiency of vitamin B₆ results in periorificial dermatitis within 3 weeks.³² Intriguingly, multiple studies have shown an inverse correlation between B₆ levels and diverse cancers, including colorectal, pancreatic, and lung cancer.²⁸

Given its role in the synthesis of nicotinic acid, vitamin B₆ deficiency results in abnormal levels of B₃. Thus, vitamin B₆ deficiency may result in a pellagra-like presentation (reviewed in detail below in the discussion of vitamin B₃ deficiency). In this case, giving vitamin B₃ does not result in significant improvement, and this failure helps to establish the diagnosis of vitamin B₆ deficiency.³² It is believed that pellagrous lesions in vitamin B₆ deficiency are due to decreased synthesis of proline from ornithine, as suggested by decreased levels of the enzyme ornithine aminotransferase in patients with low vitamin B₆.³³ Other cutaneous manifestations of vitamin B₆ deficiency include eczema and seborrheic dermatitis.³³

Vitamin B₆ can be measured in blood and urine. Although these levels only reflect recent intake, plasma values lower than 20 nmol/L are indicative of vitamin B₆ deficiency.³⁴ Therapeutic oral supplementation of vitamin B₆ is the treatment of choice. Vitamin B₆ treatment is safe, but exposure to high levels of vitamin B₆ may result in photosensitivity and dermatitis.³⁵

Vitamin B₂ (riboflavin) deficiency

Riboflavin, or vitamin B₂, is a water-soluble vitamin involved in diverse reduction-oxidation reactions. Its active forms—flavin adenine dinucleotide and flavin mononucleotide—act as electron carriers in the respiratory electron transfer chain, and the former is necessary for the oxidation of fatty acids.³⁶ The human body does not store riboflavin, and excess intake is excreted in the urine.³⁶

Milk, dairy products, and meat are the major dietary sources of vitamin B₂. Additionally, some colonic bacteria synthesize it and provide an additional source.³⁶ Patients whose diets are low in dairy and meat products, in particular vegetarians, alcoholics, and the elderly, are at risk of this deficiency. Other populations at risk are pregnant women, lactating women, premature infants, infants exposed to phototherapy for hyperbilirubinemia, and infants of mothers with low vitamin B₂ levels.^36,37

The RDA for vitamin B₂ is 1.3 mg/day for men and 1.1 mg/day per women, with higher requirements for pregnant and lactating women. Fortunately, the median intake of riboflavin from diet in the United States is 2 mg/day for men and 1.5 mg/day for women.³⁸

Features of vitamin B₂ deficiency

Features of vitamin B₂ deficiency include angular stomatitis, glossitis, cheilosis, nasolabial dermatitis, and rarely corneal vascularization.^39,40 Dermatitic lesions around the scrotum and labia are common and are in many cases the initial manifestation of vitamin B₂ deficiency.^39,40 Riboflavin deficiency during development results in muscular, skeletal, and gastrointestinal abnormalities. In adults, riboflavin deficiency is associated with anemia, decreased iron absorption, neurodegeneration, and peripheral neuropathy.³⁶

Vitamin B₂ deficiency usually coexists with other deficiencies, and riboflavin is involved in the metabolism of other B vitamins including B₃, B₆, B₉ (folate), and B₁₂. Thus, the clinical presentation of vitamin B₂ deficiency is similar to that of vitamin B₃ and B₆ deficiency (reviewed above and below) and has been described as pellagra sine pellagra (pellagra without pellagra). Moreover, correction of riboflavin deficiency results in increased levels of vitamin B₃ and B₆.³⁶

Vitamin B₂ levels can be measured in the urine and blood.³⁷ Oral supplementation is safe (up to 60 mg/day) and is the treatment of choice.^36,38 Clearance of lesions within 3 to 5 days of riboflavin supplementation confirms the diagnosis.⁴⁰

Vitamin B₃ (niacin) deficiency

Niacin, or vitamin B₃, is a water-soluble vitamin abundant in meat, eggs, and legumes. It is an essential cofactor for coenzyme I and coenzyme II; therefore, it plays a crucial role in ATP synthesis, glycolysis, and metabolism of fatty acids and amino acids.^41,42

Most niacin is acquired in the diet, but humans can synthesize it from tryptophan in the presence of vitamin B₆ and thiamine.⁴² Thus, a deficiency in tryptophan, vitamin B₆, or thiamine can also lead to low niacin, and  an excess of dietary leucine can interfere with niacin synthesis and result in deficiency.⁴²

The RDA for niacin is 6 to 20 mg/day, based on sex and age, with higher requirements for pregnant and lactating women.³⁸

Pellagra, the clinical manifestation

Pellagra is the clinical manifestation of niacin deficiency, although it is thought that lack of tryptophan, vitamin B₆, or thiamine may also be required for clinical symptoms to appear.⁴¹

Sporadic cases of pellagra occur in homeless people, alcoholics, drug abusers, people with anorexia, and food faddists.^41,42 Symptoms typically develop after about 50 days of a niacin-free diet.⁴¹ Pellagra may also develop due to impaired absorption or metabolism, particularly in patients with prolonged diarrhea, colitis, ileitis, hepatic cirrhosis, or Hartnup disease.^42–45 Certain medications, eg, isoniazid, 5-fluorouracil, azathioprine, and 6-mercaptopurine, interfere with niacin synthesis and may induce pellagra in susceptible patients.⁴²

The clinical course of pellagra is often described by the four “Ds”: dermatitis, dementia, diarrhea, and, when not corrected, death. Early symptoms of insufficient vitamin B₃ are weakness, fatigue, loss of appetite, depression, and mood changes.⁴²

The cutaneous manifestations of pellagra are impressive and include photosensitive eruptions, perineal lesions, and thickened and pigmented skin.⁴¹ Biopsy of affected and unaffected skin in pellagra patients shows abnormal keratinization.

Photosensitivity is an initial manifestation of pellagra.⁴⁶ It is believed that vitamin B₃ deficiency results in a lack of urocanic acid, a compound that protects against ultraviolet B damage and accumulation of kynurenic acid, a known phototoxic agent.⁴⁷

The initial stage of acute pellagra can resemble a sunburn on the face, neck, and dorsal extremities⁴⁷ that becomes darker with time instead of fading.⁴⁶ Sharply demarcated hyperpigmented areas on the arms and legs are known as the “glove” and “boot” of pellagra.⁴⁶ Nearly all patients have involvement of the dorsum of the hand.⁴² The Casal necklace may be present, a characteristic eruption observed in up to 76% of patients on the front of the neck in the region of C3-C4.⁴⁸

As the disease progresses, lesions harden and become brittle—hence, the name pellagra, which means “rough skin.” Perineal lesions are also common, along with fissures and ulcerations. Additionally, about a third of pellagra patients have involvement of the lips, tongue, and oral mucosa.⁴² Notably, patients with drug-induced or Hartnup-related pellagra do not develop genital, perineal, oral, or hyperkeratotic lesions.⁴⁶

Although untreated pellagra can lead to death in 5 years,⁴² the disease responds dramatically to oral nicotinamide (250–500 mg/day), which is preferred over niacin due to the latter’s vasomotor effects.⁴¹ Therapy also includes caloric supplementation, other B vitamins, zinc, and magnesium.⁴²

NUTRITIONAL DEFICIENCIES TEND TO COEXIST

The clinical scenarios presented here emphasize how different nutritional deficiencies can manifest with overlapping features. But nutritional deficiencies, particularly those associated with underlying conditions, tend to coexist rather than occur in isolation.

Although associated with significant morbidity, nutritional deficiencies can be easily addressed, particularly when promptly identified. Careful evaluation of the history and clinical and serologic findings is necessary to correctly diagnose and address these conditions.

Although vitamin and mineral deficiencies are relatively uncommon in the United States and other developed countries, physicians must be alert to them, particularly in specific populations such as infants, pregnant women, alcoholics, vegetarians, people of lower socioeconomic status, and patients on dialysis, on certain medications, or with a history of malabsorption or gastrointestinal surgery. The skin is commonly affected by nutritional deficiencies and can provide important diagnostic clues.

This article reviews the consequences of deficiencies of zinc and vitamins A, B₂, B₃, B₆, and C, emphasizing dermatologic findings.

ZINC DEFICIENCY

Case: A colon cancer patient on total parenteral nutrition

A 65-year-old woman who had been on total parenteral nutrition for 4 months after undergoing surgical debulking for metastatic colon cancer was admitted for evaluation of a rash on her face and extremities and failure to thrive. The rash had started 10 days earlier as small red papules and vesicles on the forehead and progressed to cover the forehead and lips. She had been prescribed prednisone 20 mg daily, but the condition had not improved.

Physical examination revealed numerous violaceous papules, plaques, and vesicles on her face, legs, and feet (Figure 1). The vesicles were tender to touch and some were crusted. Biopsy of a lesion on her leg revealed psoriasiform dermatitis with prominent epidermal pallor and necrosis (Figure 2), suggestive of a nutritional deficiency.

Blood testing revealed low levels of alkaline phosphatase and zinc. She was started on zinc supplementation (3 mg/kg/day), and her cutaneous lesions improved within a month, confirming the diagnosis of zinc deficiency.

Zinc is an essential trace element

Zinc is an essential trace element required for function of many metalloproteases and transcription factors involved in reproduction, immunology, and wound repair. Additionally, its antioxidant properties help prevent ultraviolet radiation damage.¹

The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women, with higher amounts for pregnant and lactating women.¹ The human body does not store zinc, and meat and eggs are the most important dietary sources.¹

The normal plasma zinc level is 70 to 250 µL/dL, and hypozincemia can be diagnosed with a blood test. For the test to be accurate, zinc-free tubes should be used, anticoagulants should be avoided, the blood should not come into contact with rubber stoppers, and blood should be drawn in the morning due to diurnal variation in zinc levels. Additionally, zinc levels may be transiently low secondary to infection. Thus, the clinical picture, along with zinc levels, histopathology, and clinical response to zinc supplementation are necessary for the diagnosis of zinc deficiency.²

Since zinc is required for the activity of alkaline phosphatase (a metalloenzyme), serum levels of alkaline phosphatase correlate with zinc levels and can be used as a serologic marker for zinc levels.³

Zinc deficiency is a worldwide problem, with a higher prevalence in developing countries. It can result from either inadequate diet or impaired absorption, which can be acquired or inherited.

Clinical forms of zinc deficiency

Acrodermatitis enteropathica, an inherited form of zinc deficiency, is due to a mutation in the SLC39A4 gene encoding a zinc uptake protein.⁴ Patients typically present during infancy a few weeks after being weaned from breast milk. Clinical presentations include diarrhea, periorificial (eg, around the mouth) and acral dermatitis, and alopecia, although only 20% of patients have all these findings at presentation.⁵ Occasionally, diaper rash, photosensitivity, nail dystrophy, angular stomatitis, conjunctivitis, blepharitis, and growth retardation are observed. Serum levels of zinc and alkaline phosphatase are low.⁵ Clinical and serologic markers improve within 2 to 3 weeks with oral zinc supplementation (2–3 mg/kg/day).

Acquired forms of zinc deficiency are linked to poor socioeconomic status, diet, infections, renal failure, pancreatic insufficiency, cystic fibrosis, and malabsorption syndromes.^1,6,7 Cutaneous findings in acquired cases of zinc deficiency are similar to those seen in acrodermatitis enteropathica. Periorificial lesions are a hallmark of this condition, and angular cheilitis is an early manifestation. Eczematous annular plaques typically develop in areas subjected to repeated friction and pressure and may evolve into vesicles, pustules, and bullae.² On biopsy study, lesions are characterized by cytoplasmic pallor, vacuolization, and necrosis of keratinocytes, which are common findings in nutritional deficiencies.⁸ Dystrophic nails, structural hair changes, and diminished growth of both hair and nails have been reported.²

Cutaneous lesions due to hypozincemia respond quickly to zinc supplementation (1–3 mg/kg/day), usually without permanent damage.² However, areas of hypo- and hyperpigmentation may persist.

VITAMIN C DEFICIENCY

Case: A lung transplant recipient on peritoneal dialysis

A 59-year-old bilateral lung transplant patient with a history of chronic kidney disease on peritoneal dialysis for the past 2 years was admitted for peritonitis. He had developed tender violaceous papules and nodules coalescing into large plaques on his arms and perifollicular purpuric macules on both legs 3 days before admission (Figure 3). The lesions were painful to the touch, and some bled at times. Tender gums, bilateral edema, and corkscrew hair were also noted (corkscrew hair is shown in another patient in Figure 4).

Biopsy of a lesion on the forearm was consistent with lymphangiectasia secondary to edema. Staining for bacteria and fungi was negative.

Serologic investigation revealed low vitamin C serum levels (7 µmol/L, reference range 23–114 µmol/L). Supplementation with 1 g/day of vitamin C was started and resulted in gradual improvement of the purpura. The patient died 4 months later of complications of comorbidities.

An important antioxidant

Vitamin C, or ascorbic acid, is an important antioxidant involved in the synthesis of tyrosine, tryptophan, and folic acid and in the hydroxylation of glycine and proline, a required step in the formation of collagen.⁹ Humans cannot synthesize vitamin C and must acquire it in the diet.⁹ Plants are the most important dietary sources.⁹ Although vitamin C is generally not toxic and its metabolites are renally cleared, diarrhea and other gastrointestinal disturbances can occur if large amounts are ingested.¹⁰

Vitamin C deficiency is rare in developed countries and is linked to malnutrition. Risk factors include alcoholism, severe psychiatric illness, anorexia, and low socioeconomic status. Moreover, multiple conditions including stress, viral illness, smoking, fever, and use of antibiotics lead to diminished vitamin C bioavailability.⁹ Patients on dialysis are at increased risk of vitamin C deficiency since it is lost during the process.¹¹

The RDA for vitamin C is 90 mg for men and 75 mg for women, with higher requirements during pregnancy and lactation.¹² This is much higher than the amount needed to prevent scurvy, 10 mg/day.¹³

Scurvy is the classic manifestation

The classic manifestations of vitamin C deficiency are scurvy and Barlow disease, also known as infantile scurvy.

Early manifestations of vitamin C deficiency such as fatigue, mood changes, and depression appear after 1 to 3 months of inadequate intake.¹³ Other manifestations are anemia, bone pain, hemorrhage into joints, abnormal vision, and possibly osteoporosis.

Cutaneous findings are a hallmark of scurvy. Follicular hyperkeratosis with fragmented corkscrew hair and perifollicular hemorrhages on posterior thighs, forearms, and abdomen are pathognomonic findings that occur early in the disease.¹³ The cutaneous hemorrhages can become palpable, particularly in the lower limbs. Diffuse petechiae are a later finding along with ecchymosis, particularly in pressure sites such as the buttocks.¹³ “Woody edema” of the legs with ecchymosis, pain, and limited motion can also arise.¹⁴ Nail findings including koilonychia and splinter hemorrhages are common.^13,14

Vitamin C deficiency results in poor wound healing with consequent ulcer formation due to impaired collagen synthesis. Hair abnormalities including corkscrew and swan-neck hairs are common in scurvy due to vitamin C’s role in disulfide bond formation, which is necessary for hair synthesis.¹³

Scurvy also affects the oral cavity: gums typically appear red, swollen, and shiny earlier in the disease and can become black and necrotic later.¹³ Loosening and loss of teeth is also common.¹³

Scurvy responds quickly to vitamin C supplementation. Patients with scurvy should receive 1 to 2 g of vitamin C daily for 2 to 3 days, 500 mg daily for the next week, and 100 mg daily for the next 1 to 3 months.¹⁵ Fatigue, pain, and confusion usually improve in the first 24 hours of treatment, cutaneous manifestations respond in 2 weeks, and hair within 1 month. Complete recovery is expected within 3 months on vitamin C supplementation.¹⁵

VITAMIN A DEFICIENCY

Case: A girl with short-bowel syndrome on total parenteral nutrition

A 14-year-old girl who had been on total parenteral nutrition for the past 3 years due to short-bowel syndrome was admitted for evaluation for a second small-bowel transplant. She complained of dry skin and dry eyes. She was found to have rough, toad-like skin with prominent brown perifollicular hyperkeratotic papules on buttocks and extremities (Figure 5). Additionally, corkscrew hairs were noted. Physical examination was consistent with phrynoderma.

Blood work revealed low levels of vitamin A (8 µg/dL, reference range 20–120 µg/dL) and vitamin C (20 µmol/L, reference range 23–114 µmol/L). After bowel transplant, her vitamin A levels normalized within 2 weeks and her skin improved without vitamin A supplementation.

Essential for protein synthesis

Vitamin A is a group of fat-soluble isoprenoids that includes retinol, retinoic acid, and beta-carotene. It is stored in hepatic stellate cells, which can release it in circulation for distribution to peripheral organs when needed.¹⁶

Vitamin A is essential for protein synthesis in the eye and is a crucial component of phototransduction.¹⁷ It is also an important modulator of the immune system, as it enhances cytotoxicity and proliferation of T cells while suppressing B-cell proliferation.¹⁸ Additionally, vitamin A plays an important role in the skin, where it promotes cell mitosis and increases epithelial thickness, the number of Langerhans cells, and glycosaminoglycan synthesis.^19–21

Deficiency associated with malabsorption, liver disease, small-bowel surgery

Vitamin A deficiency is rare in developed countries overall, but it is associated with malabsorption, liver disease, and small-bowel surgery.²² Indeed, 4 years after undergoing bariatric surgery, 69% of patients in one series had deficiencies in vitamin A and other fat-soluble vitamins.²³ The typical manifestations are nyctalopia (night blindness) and xerophthalmia (inability to produce tears).

Phrynoderma, or “toad skin,” is a cutaneous manifestation of vitamin A deficiency. The association between phrynoderma and vitamin A deficiency was established in 1933 when prisoners in Africa with nyctalopia, xerophthalmia, and phrynoderma showed improvement in all three conditions when treated with cod oil, which is rich in vitamin A.²⁴

Phrynoderma is characterized by dry, hyperkeratotic papules with central intrafollicular plugs projecting from hair follicles.²⁵ The lesions are typically symmetrically distributed on the face, the skull, and the extensor surfaces of the shoulders, buttocks, and extremities, but they can extend to the entire body in severe cases.²⁵ They typically get better with improved nutrition.

Evidence is mounting to suggest phrynoderma is a cutaneous manifestation of diverse nutritional deficiencies, not just vitamin A. For example, some children with phrynoderma have normal levels of vitamin A,²⁶ and a trial showed that patients with phrynoderma benefited from intramuscular injections of either vitamin A or vitamin B complex, particularly when also treated with topical keratolytics.²⁷ Thus, patients who present with the typical lesions of phrynoderma should be screened for nutritional deficiencies beyond vitamin A.

VITAMIN B₆ DEFICIENCY

Case: A woman with sepsis

A 62-year-old woman with a 4-year history of unspecified dermatitis, intertriginous rashes, and skin ulcerations with polymicrobial infections was admitted for sepsis. She reported that her rash had worsened over the previous 2 weeks. Physical examination revealed generalized xerosis, an inflamed bright red tongue with atrophy of distal papillae, and red painful erosions in intertriginous areas (Figure 6).

Blood testing revealed low levels of vitamin B₂ (< 5.0 nmol/L, reference range 6.2–39 nmol/L) and vitamin B₆ (3.1 nmol/L, reference range 20–125 nmol/L). She was started on supplementation with vitamin B₆ 50 mg/day and vitamin B₂ 200 mg/day, and her dermatitis and ulcers improved.

Pyridoxine and its derivatives

Pyridoxine and its derivatives are collectively known as vitamin B₆. Vitamin B₆ can be stored throughout the body, particularly in muscle and the liver, whereas its oxidized version is excreted mostly in the urine.^28,29 Vitamin B₆ serves as a cofactor to more than 140 enzymes, it is required for tryptophan metabolism and synthesis of nicotinic acid, and it is a cofactor for alanine aminotransferase and aspartate aminotransferase.^28,29

Vitamin B₆ deficiency is rare in the general population. The median daily intake is 2 mg/day for men and 1.5 mg/day for women, whereas the RDA for adults is 1.3 mg/day. No signs of vitamin B₆ deficiency have been noted at intakes greater than 0.5 mg/day in clinical studies.²⁸

However, chronic alcoholism poses a high risk of this deficiency because it decreases the intake of vitamin B₆ and decreases the ability of the liver to store it. Additionally, patients with eclampsia or preeclampsia or who are on dialysis have higher vitamin B₆ requirements.²⁸ Certain medications are also associated with a low vitamin B₆ level, in particular the antituberculosis medication isoniazid, penicillamine, and hydralazine.²⁸

Although clinical manifestations of vitamin B₆ deficiency are rare, subclinical deficiency may be common, particularly in the elderly,²⁸ as up to 23% of people ages 65 to 75 and 40% of those older than 85 have vitamin B₆ deficiency.^30,31

Features of vitamin B₆ deficiency

Vitamin B₆ deficiency is associated with anemia (hypochromic, microcytic, iron-refractory), impaired immune function, seizures, peripheral neuropathy, and glossitis. Experimentally induced deficiency of vitamin B₆ results in periorificial dermatitis within 3 weeks.³² Intriguingly, multiple studies have shown an inverse correlation between B₆ levels and diverse cancers, including colorectal, pancreatic, and lung cancer.²⁸

Given its role in the synthesis of nicotinic acid, vitamin B₆ deficiency results in abnormal levels of B₃. Thus, vitamin B₆ deficiency may result in a pellagra-like presentation (reviewed in detail below in the discussion of vitamin B₃ deficiency). In this case, giving vitamin B₃ does not result in significant improvement, and this failure helps to establish the diagnosis of vitamin B₆ deficiency.³² It is believed that pellagrous lesions in vitamin B₆ deficiency are due to decreased synthesis of proline from ornithine, as suggested by decreased levels of the enzyme ornithine aminotransferase in patients with low vitamin B₆.³³ Other cutaneous manifestations of vitamin B₆ deficiency include eczema and seborrheic dermatitis.³³

Vitamin B₆ can be measured in blood and urine. Although these levels only reflect recent intake, plasma values lower than 20 nmol/L are indicative of vitamin B₆ deficiency.³⁴ Therapeutic oral supplementation of vitamin B₆ is the treatment of choice. Vitamin B₆ treatment is safe, but exposure to high levels of vitamin B₆ may result in photosensitivity and dermatitis.³⁵

Vitamin B₂ (riboflavin) deficiency

Riboflavin, or vitamin B₂, is a water-soluble vitamin involved in diverse reduction-oxidation reactions. Its active forms—flavin adenine dinucleotide and flavin mononucleotide—act as electron carriers in the respiratory electron transfer chain, and the former is necessary for the oxidation of fatty acids.³⁶ The human body does not store riboflavin, and excess intake is excreted in the urine.³⁶

Milk, dairy products, and meat are the major dietary sources of vitamin B₂. Additionally, some colonic bacteria synthesize it and provide an additional source.³⁶ Patients whose diets are low in dairy and meat products, in particular vegetarians, alcoholics, and the elderly, are at risk of this deficiency. Other populations at risk are pregnant women, lactating women, premature infants, infants exposed to phototherapy for hyperbilirubinemia, and infants of mothers with low vitamin B₂ levels.^36,37

The RDA for vitamin B₂ is 1.3 mg/day for men and 1.1 mg/day per women, with higher requirements for pregnant and lactating women. Fortunately, the median intake of riboflavin from diet in the United States is 2 mg/day for men and 1.5 mg/day for women.³⁸

Features of vitamin B₂ deficiency

Features of vitamin B₂ deficiency include angular stomatitis, glossitis, cheilosis, nasolabial dermatitis, and rarely corneal vascularization.^39,40 Dermatitic lesions around the scrotum and labia are common and are in many cases the initial manifestation of vitamin B₂ deficiency.^39,40 Riboflavin deficiency during development results in muscular, skeletal, and gastrointestinal abnormalities. In adults, riboflavin deficiency is associated with anemia, decreased iron absorption, neurodegeneration, and peripheral neuropathy.³⁶

Vitamin B₂ deficiency usually coexists with other deficiencies, and riboflavin is involved in the metabolism of other B vitamins including B₃, B₆, B₉ (folate), and B₁₂. Thus, the clinical presentation of vitamin B₂ deficiency is similar to that of vitamin B₃ and B₆ deficiency (reviewed above and below) and has been described as pellagra sine pellagra (pellagra without pellagra). Moreover, correction of riboflavin deficiency results in increased levels of vitamin B₃ and B₆.³⁶

Vitamin B₂ levels can be measured in the urine and blood.³⁷ Oral supplementation is safe (up to 60 mg/day) and is the treatment of choice.^36,38 Clearance of lesions within 3 to 5 days of riboflavin supplementation confirms the diagnosis.⁴⁰

Vitamin B₃ (niacin) deficiency

Niacin, or vitamin B₃, is a water-soluble vitamin abundant in meat, eggs, and legumes. It is an essential cofactor for coenzyme I and coenzyme II; therefore, it plays a crucial role in ATP synthesis, glycolysis, and metabolism of fatty acids and amino acids.^41,42

Most niacin is acquired in the diet, but humans can synthesize it from tryptophan in the presence of vitamin B₆ and thiamine.⁴² Thus, a deficiency in tryptophan, vitamin B₆, or thiamine can also lead to low niacin, and  an excess of dietary leucine can interfere with niacin synthesis and result in deficiency.⁴²

The RDA for niacin is 6 to 20 mg/day, based on sex and age, with higher requirements for pregnant and lactating women.³⁸

Pellagra, the clinical manifestation

Pellagra is the clinical manifestation of niacin deficiency, although it is thought that lack of tryptophan, vitamin B₆, or thiamine may also be required for clinical symptoms to appear.⁴¹

Sporadic cases of pellagra occur in homeless people, alcoholics, drug abusers, people with anorexia, and food faddists.^41,42 Symptoms typically develop after about 50 days of a niacin-free diet.⁴¹ Pellagra may also develop due to impaired absorption or metabolism, particularly in patients with prolonged diarrhea, colitis, ileitis, hepatic cirrhosis, or Hartnup disease.^42–45 Certain medications, eg, isoniazid, 5-fluorouracil, azathioprine, and 6-mercaptopurine, interfere with niacin synthesis and may induce pellagra in susceptible patients.⁴²

The clinical course of pellagra is often described by the four “Ds”: dermatitis, dementia, diarrhea, and, when not corrected, death. Early symptoms of insufficient vitamin B₃ are weakness, fatigue, loss of appetite, depression, and mood changes.⁴²

The cutaneous manifestations of pellagra are impressive and include photosensitive eruptions, perineal lesions, and thickened and pigmented skin.⁴¹ Biopsy of affected and unaffected skin in pellagra patients shows abnormal keratinization.

Photosensitivity is an initial manifestation of pellagra.⁴⁶ It is believed that vitamin B₃ deficiency results in a lack of urocanic acid, a compound that protects against ultraviolet B damage and accumulation of kynurenic acid, a known phototoxic agent.⁴⁷

The initial stage of acute pellagra can resemble a sunburn on the face, neck, and dorsal extremities⁴⁷ that becomes darker with time instead of fading.⁴⁶ Sharply demarcated hyperpigmented areas on the arms and legs are known as the “glove” and “boot” of pellagra.⁴⁶ Nearly all patients have involvement of the dorsum of the hand.⁴² The Casal necklace may be present, a characteristic eruption observed in up to 76% of patients on the front of the neck in the region of C3-C4.⁴⁸

As the disease progresses, lesions harden and become brittle—hence, the name pellagra, which means “rough skin.” Perineal lesions are also common, along with fissures and ulcerations. Additionally, about a third of pellagra patients have involvement of the lips, tongue, and oral mucosa.⁴² Notably, patients with drug-induced or Hartnup-related pellagra do not develop genital, perineal, oral, or hyperkeratotic lesions.⁴⁶

Although untreated pellagra can lead to death in 5 years,⁴² the disease responds dramatically to oral nicotinamide (250–500 mg/day), which is preferred over niacin due to the latter’s vasomotor effects.⁴¹ Therapy also includes caloric supplementation, other B vitamins, zinc, and magnesium.⁴²

NUTRITIONAL DEFICIENCIES TEND TO COEXIST

The clinical scenarios presented here emphasize how different nutritional deficiencies can manifest with overlapping features. But nutritional deficiencies, particularly those associated with underlying conditions, tend to coexist rather than occur in isolation.

Although associated with significant morbidity, nutritional deficiencies can be easily addressed, particularly when promptly identified. Careful evaluation of the history and clinical and serologic findings is necessary to correctly diagnose and address these conditions.

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

The article “Anemia of chronic kidney disease: Treat it, but not too aggressively” by Drs. Georges Nakhoul and James F. Simon (Cleve Clin J Med 2016; 83:613–624) contained a typographical error. In Table 2, the target ferritin level in chronic kidney disease is given as greater than 100 ng/dL, and for end-stage renal disease 200 to 1,200 ng/dL. Ferritin levels are measured in ng/mL, not ng/dL.

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

In Reply: We thank Dr. Keller for his thorough reading of our article.¹

Regarding the predictive value of neck circumference for obstructive sleep apnea, (OSA), neck circumference is one of many tools to screen for OSA. If neck circumference greater than 38 cm is applied without other predictors (such as the presence of snoring, daytime sleepiness, or elevated body mass index), it provides only a 58% sensitivity and 79% specificity.² It is less an issue of inches vs collar size vs centimeters than of combining circumference with other parameters (as in the STOP-BANG questionnaire) before proceeding with a sleep study. The senior author of our article (G.R.) uses 38 cm.

With respect to home vs sleep lab monitoring, the question was beyond the scope of the paper and outside our expertise, as we are both general internists. The home venue recommendations in this instance were taken directly from the American Academy of Sleep Medicine.³ We would rely on consultation with a sleep specialist before ordering home monitoring to determine the potential success of non-CPAP interventions for OSA.

As for Parkinson disease as an exception to OSA and hypertension, we wrote in the paper, “Untreated OSA is associated with a number of conditions.”¹ Yes, resistant hypertension is prominent in today’s epidemic of obesity, diabetes, and OSA, but not everyone with coronary artery disease, atrial fibrillation, or heart failure—as in persons with Parkinson disease—has hypertension. The associated conditions in our paper are more typical of a general medical practice, but we agree that Parkinson disease is associated with OSA. Patients with hypertension and OSA are more prevalent because the clinical risk factors for OSA and hypertension are common to both conditions.⁴

In adults, apnea is considered present when the airflow drops by 90% or more from the pre-event baseline. Hypopnea in adults is present when the airflow drops by 30% or more of the pre-event baseline for 10 or more seconds in association with either 3% or greater arterial oxygen desaturation or an electroencephalographic arousal.⁵ Studies have shown that episodes of hypopnea with 2% oxygen desaturation are associated with an increased prevalence of metabolic impairment.⁶ A higher degree of desaturation, ie, more than 4%, was associated with increased prevalence of self-reported cardiovascular disease.⁷ But the significance of episodes of hypopnea without arterial desaturation is not well known to us and was beyond the scope of our article.

Our article was primarily focused on screening for OSA in ambulatory clinical practice and was not intended as a comprehensive review of screening in different settings of patient care. As to the importance of recognizing OSA in patients undergoing elective surgery under general anesthesia, we agree that screening is important to reduce the risk of postoperative adverse respiratory events in patients with a high pretest probability of OSA. In a recent study by Seet et al,⁸ patients with high STOP-BANG questionnaire scores (≥ 3) had higher rates of intraoperative and early postoperative adverse events than those with low scores (< 3). The risk of adverse events correlated with higher scores, and  patients with a STOP-BANG score of 5 or more had a five times greater risk of unexpected intraoperative and early postoperative adverse events, whereas those with a STOP-BANG score of 3 or more had a one in four chance of an adverse event. We recommend polysomnography for patients with a STOP-BANG score of 5 or more before elective surgery.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

—Robert Frost, “Stopping by Woods on a Snowy Evening”¹

Frost's words are simple yet elegant. They can be interpreted many ways. I see the allegory of life as a journey in this poem. The passage, like the woods, is beautiful, but there is a long, long way to go.

See related article

And so it is with the treatment of heart failure. There is beauty in our understanding of the syndrome’s physiologic complexities and natural history, and of effective treatments uncovered. Still, we’ve a monstrous climb ahead to get to the summit of this clinical challenge in order to start a real descent.

THE PAST, PRESENT, AND FUTURE OF HEART FAILURE THERAPY

Okwuosa et al,² in this issue of the Journal, have capably summarized the ABCs of treating heart failure with reduced ejection fraction (also called systolic heart failure), approaching the subject from a perspective on past, present, and future therapies. They summarize heart failure interventions with a guideline-based philosophy, pointing out that these care paths are supposed to be evidence-based. They observe that in the 1960s the standard of care was digitalis, diuretics (furosemide first became available in 1967), and rest. That was about all we had for this problem.

There are now many drugs, devices, and operations that help patients with heart failure. But they never really cure the disease or, more aptly, the syndrome—and therapies are supposed to cure. This limitation of present therapies is important, given the disturbing epidemiology of heart failure, its economic cost, and the suffering of patients. That burden is well detailed.

In addition to curing, the overarching goals of treatment generally are to ameliorate distressing symptoms and to prevent comorbidities. In heart failure with reduced ejection fraction, we want to prevent premature death, stroke, myocardial infarction, congestive states, hospitalization, renal insufficiency, renal failure, cachexia, inanition, feebleness, and respiratory distress, among others.

The ABC mnemonic of Okwuosa et al will help caregivers remember the basics. It is important, however, to put algorithms into proper perspective and to look toward the future.

PROBLEMS WITH EVIDENCE-BASED MEDICINE

Several problems with our current heart failure treatments are rooted in how we perform clinical trials, arguably the premier method of determining truth in clinical practice and the foundation of evidence-based medicine.^3,4

Do the trials represent real-world practice?

Were the clinical trials that led to regulatory approval and professional society endorsement of the therapies that we prescribe in our offices done in the same sorts of patients as those in our waiting rooms asking for help? Perhaps, for the most part, they have been. And thus, Okwuosa et al have crafted a work relevant to all of us and every patient.

But I believe there are major gaps in the types of participants enrolled in trials, eg, underrepresentation of certain racial and ethnic groups, not to mention the relative paucity of women. The very elderly (a rapidly growing population) have largely been ignored as well, and participants with significant renal insufficiency, anemia, and diabetes mellitus seem far fewer than what we deal with in a busy clinic.

In addition, Okwuosa et al focus only on patients with reduced left ventricular ejection fraction, a group that makes up only about half of the heart failure crowd.

What about quality of life and other important outcomes?

Clinical trials in heart failure with reduced ejection fraction have generally focused on major clinical end points (primarily, but not exclusively, mortality), to the exclusion of quality of life. Though sometimes included in trials, quality-of-life metrics generally get relegated to second-class seats or ‘tween-deck steerage. Perhaps that is because measuring quality of life can be time-consuming and difficult.

Yet, in the words of sociologist William Bruce Cameron, not everything that counts can be counted, and not everything that can be counted counts. That goes for quality of life.

Lies, damned lies, and P values

Quandaries in data management and analysis include what to do about trial dropouts, study power, precision of statistical analysis, intention-to-treat principles, and choice of the P value that defines significance (or not) for any end point observation. Of course, there are myriad sophisticated mathematical and statistical reasons to justify why we don’t simply count on-treatment participants or allow imputation of results when patients or results drop out, forcing us to worship at the altar of P < .05.

A review of the P value concept⁵ recently appeared with an accompanying editorial by Kyriacou⁶ that concluded that “the automatic application of dichotomized hypothesis testing based on prearranged levels of statistical significance should be substituted with a more complex process using effect estimates, confidence intervals, and even P values, thereby permitting scientists, statisticians, and clinicians to use their own inferential capabilities to assign scientific significance.”⁶

How many great treatments have we tossed out because of rigid reliance on old-fashioned approaches to determining therapeutic evidence? Many treatments studied have had great results in a minority of patients in clinical trials but did not have a major positive (or negative) impact on the overall cohort (with lack of primary end point statistical significance). And what to do when the primary end point is a neutral or negative one but secondary end points are positive? Why not focus more attention on those patients benefiting from an intervention despite the overall results of any trial?

Dilemmas of trials

Other issues are that clinical trials cost too much, and that recruitment and follow-up take too long. Intercurrent therapies (and guidelines) can emerge that jeopardize the trial itself or make observations untimely. The dilemma of stacking therapies one on top of another, often making patient compliance impossible, is another problem with clinical trials. Yet this is how we get to the ABCs.

A NEW WAY TO DO TRIALS

The information provided by Okwuosa et al is useful and encouraging, but too many gaps exist in our heart failure therapies to permit us to celebrate with exuberance. Too many patients still suffer, too many die too young, and the costs are still too great.

Perhaps the future of therapeutic development should embrace different and better ways to demonstrate real value (relying on the equation of value equals outcomes meaningful to patients, divided by cost) of therapies, including the old, the new, the trashed and the underdeveloped. More creative data analysis to reexamine the current tools on the shelf and the ones tried but discarded is essential.

A position paper from the Cardiovascular Round Table of the European Society of Cardiology concluded that “a coordinated effort involving academia, regulators, industry and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.”⁷

Lauer and D’Agostino,⁸ also in an editorial, argued for innovative methods of doing clinical trials and discovering truth about therapies that are applicable to the future of developing treatments for heart failure with reduced ejection fraction. They noted that “the randomized registry trial represents a disruptive technology” and wondered if it will be “given serious consideration as a way to resolve the recognized limitations of current clinical-trial design.”⁸

Indeed, conducting megatrials with existing megadatabases using a registry format could help. Registries emerging from early adaptive trial design efforts, particularly when Bayesian analysis theory is applied, might help inform clinical experience faster and more efficiently. Bayesian analysis is a statistical approach that attempts to estimate parameters of an underlying distribution of events in an ongoing fashion based on the observed distribution. A clinical trial of stem cell therapies could, at the end of the trial, be turned into a multicenter registry that would continue to inform us about the more real-world application of newer treatment approaches.

Though the therapeutic cupboard for heart failure is certainly not bare, as Okwuosa et al point out, it is wanting. Let’s look for new therapeutic ABCs differently. We should be attacking the real challenge—curing the disease processes that cause the syndrome. Yes, there are miles to go before we sleep.