Case Reports

Langerhans cell histiocytosis (LCH), also known as histiocytosis X, is a general term that describes a group of rare disorders characterized by the proliferation of Langerhans cells.¹ Central to immune surveillance and the elimination of foreign substances from the body, Langerhans cells are derived from bone marrow progenitor cells and found in the epidermis but are capable of migrating from the skin to the lymph nodes. In LCH, these cells congregate on bone tissue, particularly in the head and neck region, causing a multitude of problems.²

The spectrum of LCH includes 4 variants: congenital self-healing reticulohistiocytosis (CSHR)(also known as Hashimoto-Pritzker disease), Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma (also known as pulmonary histiocytosis X)(Table). Despite the various clinical presentations and levels of severity, all variants are caused by the proliferation of Langerhans cells. We present a case of CSHR in a 6-month-old male infant that was initially diagnosed as molluscum contagiosum. We believe the actual incidence of CSHR may be underreported due to its spontaneous regression and low rate of clinical recognition.

Case Report

A 6-month-old male infant was referred to our clinic by his pediatrician with a generalized cutaneous eruption of 3 weeks’ duration. The eruption, which followed a recent viral upper respiratory tract infection, was characterized by multiple flesh-colored to erythematous, umbilicated papules distributed along the postauricular region, scalp (Figure 1A), abdomen (Figure 1B), and anterior aspect of the neck. Due to his recent illness, the patient was diagnosed with molluscum contagiosum by the referring pediatrician that was treated symptomatically with hydrocortisone lotion, Schamberg’s cream formulated in our office (a compound mixture of zinc oxide, menthol, calcium hydroxide solution, and olive oil), and pediatric diphenhydramine as needed. During a subsequent visit 2 weeks later, a more potent topical corticosteroid and a low-dose systemic corticosteroid was prescribed for 1 week due to development of new lesions and exacerbation of existing lesions. On follow-up 1 week later, the lesions on the trunk had improved, but the patient had developed new lesions on the scalp that differed from prior findings in that they were darker (more erythematous to brown) and firmer (papules and nodules).

Figure 1. Multiple fleshcolored to erythematous, umbilicated papules on the frontal scalp (A) and erythematous papules on the abdomen (B).

A shave biopsy was obtained from the frontal scalp to rule out LCH. Histologic examination and culture of the biopsy specimen revealed an atypical cellular infiltrate effacing the dermoepidermal junction and extensive epidermotropism. Focal erosion of the epidermis and an acute inflammatory exudate were visible. The nuclei of the cellular infiltrate were enlarged and hyperchromatic with a characteristic reniform appearance and indistinct nucleoli (Figure 2). The cells were admixed with scattered eosinophils and extravasated red blood cells.

Figure 2. Low-power view of dermal mononuclear cells with reniform nuclei (A)(H&E, original magnification ×100), and high-power view of enlarged and hyperchromatic nuclei with a characteristic reniform appearance admixed with eosinophils and extravasated red blood cells (B) (H&E, original magnification ×400).

Immunohistochemical staining of the biopsy specimen was strongly positive for both CD1a and S-100 expression (Figure 3). Histopathologic findings were consistent with LCH. Clinicopathologic correlation strongly favored the diagnosis of CSHR.

Comment

Congenital self-healing reticulohistiocytosis is a rare, benign, congenital variant of LCH that spontaneously resolves with no systemic involvement. The more aggressive forms typically manifest at birth or during the first 2 months of life and regress within 3 to 4 months.⁵ Since CSHR was first described in 1973 by Hashimoto and Pritzker,⁵ more than 100 cases have been reported, but the true incidence is believed to be higher than reported given the high rate of spontaneous resolution and the low rate of clinical recognition.² The first reported case of CSHR occurred in a female infant who presented at birth with multiple, diffusely distributed, red-brown papules that were 2 to 4 mm in diameter. Although the patient received no treatment, the exanthem completely resolved within 3.5 months without recurrence at 14-year follow-up.⁵ Most often, CSHR presents as multiple papules or nodules with occasional disseminated crusting and is followed within a few months by a dramatic and spontaneous regression. Lesions may heal with mild postinflammatory hyperpigmentation. Pseudo-Darier sign, the propensity to urticate from physical manipulation, has been reported in some lesions with an increased number of mast cells.⁶ Extensive superficial nasal and oral mucosal erosions have been reported in 2 cases.⁷ Solitary lesions have been reported in 25% of cases.⁸

The etiology of CSHR remains unknown, though neoplastic, viral, and immunologic origins have been suggested. There have been reports that human herpesvirus 6 may contribute to the development of LCH.⁹ It may be postulated that our patient’s presentation of CSHR was potentiated by his recent upper respiratory tract illness. In the literature, CSHR is distributed equally among males and females. Prevalence is higher in the white population than in other racial groups.⁵

Although CSHR is a benign cutaneous variant of LCH, there have been reports of patients with disseminated and extracutaneous involvement. In 1 rare case, CSHR reportedly involved the eyes, producing multiple, bilateral, well-circumscribed, diffuse, yellow-white lesions of the retinal pigment epithelium throughout the posterior pole of the eyes.¹⁰ The retinal lesions spontaneously regressed along with the skin manifestations. Additionally, it was reported that a neonate in Thailand presented with CSHR at birth and 1 month later developed multiple lung cysts that had completely regressed 11 months later.¹¹ One study reported that initial diagnoses of LCH in 18 patients with only cutaneous involvement eventually progressed to systemic LCH, requiring further management.¹² When LCH is suspected, a thorough physical examination, including hematologic and coagulation evaluation, liver function tests, musculoskeletal examination, and consultation with specialists if necessary, is recommended.¹³

There are 3 additional variants of LCH. Letterer-Siwe disease is an acute form of LCH that accounts for 10% of all LCH cases and typically presents in children younger than 2 years. It involves multiple organs, including the bones, lungs, liver, and lymph nodes.¹⁴ Affected patients usually present with fever; hepatosplenomegaly; anemia; lymphadenopathy; extensive lytic skull lesions; and a generalized cutaneous eruption, appearing as a maculopapular scaling rash with underlying purpura on the scalp, neck, axilla, and trunk.³ Letterer-Siwe disease is inherited in an autosomal-recessive pattern. Diagnosis is confirmed by skin biopsy demonstrating a thinning of the epidermis and a collection of reticulum cells in the dermis.³ Letterer-Siwe disease is treated with radiation and chemotherapy; if left untreated, the disease is fatal.⁴

Hand-Schüller-Christian disease, a chronic form of LCH, is most commonly seen in children aged 2 to 6 years and accounts for 15% to 20% of all LCH cases. This LCH variant presents with a classic triad of diabetes insipidus (resulting from erosion into the sella turcica), lytic bone lesions, and exophthalmos.¹⁵ Hand-Schüller-Christian disease also affects the oral cavity, producing nodular ulcerations of the hard palate, trouble swallowing, and halitosis.⁴ The involvement of lytic bone lesions of the mastoid process and petrous portions of the temporal bones may cause recurrent or chronic otitis media and otitis externa. Hand-Schüller-Christian disease is treated with a combination of chemotherapy, radiation, and surgical excision. The mortality rate is 30%.⁴

Eosinophilic granuloma is the most prevalent variant of LCH, accounting for 60% to 80% of all cases. Characterized by Langerhans cell granulomatous infiltration of the lungs and painful cystic bone lesions, eosinophilic granuloma primarily presents in the third or fourth decades of life.¹⁶ Some studies suggest an epidemiologic association with tobacco use.¹⁷ In the preliminary stages of this disease, Langerhans cells, eosinophils, lymphocytes, and fibroblasts infiltrate and form nodules on the terminal bronchioles in the upper and middle lung zones, damaging the airway walls.¹⁸ Fibrotic scarring progresses, ultimately resulting in alveolar destruction.¹⁰ The common signs and symptoms of eosinophilic granuloma are a nonproductive cough, dyspnea, weight loss, spontaneous pneumothorax, fever, peripheral edema, and a tricuspid regurgitation murmur.¹⁴ The prognosis of eosinophilic granuloma is variable. Although some patients progress to end-stage fibrotic lung disease requiring lung transplant, there have been reports of complete remission following cessation of cigarette smoking.¹⁷

Langerhans cells travel from the bone marrow to the epidermis where they express the CD1a protein on the surface of the antigen-presenting cell. Elevated levels of cytokines, such as tumor necrosis factor α, IFN-γ, granulocyte-macrophage colony-stimulating factor, and interleukins have been seen in patients with LCH.¹ Their role in the pathogenesis of this disease remains unknown, but the elevated levels of cytokines may indicate the lack of an efficient immune system.

Histologically, hematoxylin and eosin–stained sections demonstrate an infiltrate of histiocytes, neutrophils, eosinophils, and an increased number of mast cells involving the papillary and reticular dermis. Infiltrating Langerhans cells have concave reniform nuclei¹⁸ and stain positive for CD1a, S-100, and CD68 antigens.¹⁵ In 10% to 30% of CSHR cases, Birbeck granules can be seen on electron microscopy and tend to transform into laminated dense bodies, signifying the degenerative changes seen in CSHR.¹⁵ The various forms of LCH exhibit no significant differences in the expression of the epithelial cadherin, the phosphorylated histone H3, and the Ki-67 proteins, indicating that they are simply different forms of the same disease represented on a spectrum.¹⁵

Conclusion

The actual incidence of CSHR may be notably underreported due to its spontaneous regression and low rate of clinical recognition. A subtype of LCH, CSHR is a diagnosis of exclusion. Although CSHR generally follows a benign clinical course, a thorough workup and evaluation for systemic disease with close follow-up is recommended after diagnosis due to the potential of LCH to involve multiple organs and to relapse at a later date after apparent regression.

Langerhans cell histiocytosis (LCH), also known as histiocytosis X, is a general term that describes a group of rare disorders characterized by the proliferation of Langerhans cells.¹ Central to immune surveillance and the elimination of foreign substances from the body, Langerhans cells are derived from bone marrow progenitor cells and found in the epidermis but are capable of migrating from the skin to the lymph nodes. In LCH, these cells congregate on bone tissue, particularly in the head and neck region, causing a multitude of problems.²

The spectrum of LCH includes 4 variants: congenital self-healing reticulohistiocytosis (CSHR)(also known as Hashimoto-Pritzker disease), Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma (also known as pulmonary histiocytosis X)(Table). Despite the various clinical presentations and levels of severity, all variants are caused by the proliferation of Langerhans cells. We present a case of CSHR in a 6-month-old male infant that was initially diagnosed as molluscum contagiosum. We believe the actual incidence of CSHR may be underreported due to its spontaneous regression and low rate of clinical recognition.

Case Report

A 6-month-old male infant was referred to our clinic by his pediatrician with a generalized cutaneous eruption of 3 weeks’ duration. The eruption, which followed a recent viral upper respiratory tract infection, was characterized by multiple flesh-colored to erythematous, umbilicated papules distributed along the postauricular region, scalp (Figure 1A), abdomen (Figure 1B), and anterior aspect of the neck. Due to his recent illness, the patient was diagnosed with molluscum contagiosum by the referring pediatrician that was treated symptomatically with hydrocortisone lotion, Schamberg’s cream formulated in our office (a compound mixture of zinc oxide, menthol, calcium hydroxide solution, and olive oil), and pediatric diphenhydramine as needed. During a subsequent visit 2 weeks later, a more potent topical corticosteroid and a low-dose systemic corticosteroid was prescribed for 1 week due to development of new lesions and exacerbation of existing lesions. On follow-up 1 week later, the lesions on the trunk had improved, but the patient had developed new lesions on the scalp that differed from prior findings in that they were darker (more erythematous to brown) and firmer (papules and nodules).

Figure 1. Multiple fleshcolored to erythematous, umbilicated papules on the frontal scalp (A) and erythematous papules on the abdomen (B).

A shave biopsy was obtained from the frontal scalp to rule out LCH. Histologic examination and culture of the biopsy specimen revealed an atypical cellular infiltrate effacing the dermoepidermal junction and extensive epidermotropism. Focal erosion of the epidermis and an acute inflammatory exudate were visible. The nuclei of the cellular infiltrate were enlarged and hyperchromatic with a characteristic reniform appearance and indistinct nucleoli (Figure 2). The cells were admixed with scattered eosinophils and extravasated red blood cells.

Figure 2. Low-power view of dermal mononuclear cells with reniform nuclei (A)(H&E, original magnification ×100), and high-power view of enlarged and hyperchromatic nuclei with a characteristic reniform appearance admixed with eosinophils and extravasated red blood cells (B) (H&E, original magnification ×400).

Immunohistochemical staining of the biopsy specimen was strongly positive for both CD1a and S-100 expression (Figure 3). Histopathologic findings were consistent with LCH. Clinicopathologic correlation strongly favored the diagnosis of CSHR.

Comment

Congenital self-healing reticulohistiocytosis is a rare, benign, congenital variant of LCH that spontaneously resolves with no systemic involvement. The more aggressive forms typically manifest at birth or during the first 2 months of life and regress within 3 to 4 months.⁵ Since CSHR was first described in 1973 by Hashimoto and Pritzker,⁵ more than 100 cases have been reported, but the true incidence is believed to be higher than reported given the high rate of spontaneous resolution and the low rate of clinical recognition.² The first reported case of CSHR occurred in a female infant who presented at birth with multiple, diffusely distributed, red-brown papules that were 2 to 4 mm in diameter. Although the patient received no treatment, the exanthem completely resolved within 3.5 months without recurrence at 14-year follow-up.⁵ Most often, CSHR presents as multiple papules or nodules with occasional disseminated crusting and is followed within a few months by a dramatic and spontaneous regression. Lesions may heal with mild postinflammatory hyperpigmentation. Pseudo-Darier sign, the propensity to urticate from physical manipulation, has been reported in some lesions with an increased number of mast cells.⁶ Extensive superficial nasal and oral mucosal erosions have been reported in 2 cases.⁷ Solitary lesions have been reported in 25% of cases.⁸

The etiology of CSHR remains unknown, though neoplastic, viral, and immunologic origins have been suggested. There have been reports that human herpesvirus 6 may contribute to the development of LCH.⁹ It may be postulated that our patient’s presentation of CSHR was potentiated by his recent upper respiratory tract illness. In the literature, CSHR is distributed equally among males and females. Prevalence is higher in the white population than in other racial groups.⁵

Although CSHR is a benign cutaneous variant of LCH, there have been reports of patients with disseminated and extracutaneous involvement. In 1 rare case, CSHR reportedly involved the eyes, producing multiple, bilateral, well-circumscribed, diffuse, yellow-white lesions of the retinal pigment epithelium throughout the posterior pole of the eyes.¹⁰ The retinal lesions spontaneously regressed along with the skin manifestations. Additionally, it was reported that a neonate in Thailand presented with CSHR at birth and 1 month later developed multiple lung cysts that had completely regressed 11 months later.¹¹ One study reported that initial diagnoses of LCH in 18 patients with only cutaneous involvement eventually progressed to systemic LCH, requiring further management.¹² When LCH is suspected, a thorough physical examination, including hematologic and coagulation evaluation, liver function tests, musculoskeletal examination, and consultation with specialists if necessary, is recommended.¹³

There are 3 additional variants of LCH. Letterer-Siwe disease is an acute form of LCH that accounts for 10% of all LCH cases and typically presents in children younger than 2 years. It involves multiple organs, including the bones, lungs, liver, and lymph nodes.¹⁴ Affected patients usually present with fever; hepatosplenomegaly; anemia; lymphadenopathy; extensive lytic skull lesions; and a generalized cutaneous eruption, appearing as a maculopapular scaling rash with underlying purpura on the scalp, neck, axilla, and trunk.³ Letterer-Siwe disease is inherited in an autosomal-recessive pattern. Diagnosis is confirmed by skin biopsy demonstrating a thinning of the epidermis and a collection of reticulum cells in the dermis.³ Letterer-Siwe disease is treated with radiation and chemotherapy; if left untreated, the disease is fatal.⁴

Hand-Schüller-Christian disease, a chronic form of LCH, is most commonly seen in children aged 2 to 6 years and accounts for 15% to 20% of all LCH cases. This LCH variant presents with a classic triad of diabetes insipidus (resulting from erosion into the sella turcica), lytic bone lesions, and exophthalmos.¹⁵ Hand-Schüller-Christian disease also affects the oral cavity, producing nodular ulcerations of the hard palate, trouble swallowing, and halitosis.⁴ The involvement of lytic bone lesions of the mastoid process and petrous portions of the temporal bones may cause recurrent or chronic otitis media and otitis externa. Hand-Schüller-Christian disease is treated with a combination of chemotherapy, radiation, and surgical excision. The mortality rate is 30%.⁴

Eosinophilic granuloma is the most prevalent variant of LCH, accounting for 60% to 80% of all cases. Characterized by Langerhans cell granulomatous infiltration of the lungs and painful cystic bone lesions, eosinophilic granuloma primarily presents in the third or fourth decades of life.¹⁶ Some studies suggest an epidemiologic association with tobacco use.¹⁷ In the preliminary stages of this disease, Langerhans cells, eosinophils, lymphocytes, and fibroblasts infiltrate and form nodules on the terminal bronchioles in the upper and middle lung zones, damaging the airway walls.¹⁸ Fibrotic scarring progresses, ultimately resulting in alveolar destruction.¹⁰ The common signs and symptoms of eosinophilic granuloma are a nonproductive cough, dyspnea, weight loss, spontaneous pneumothorax, fever, peripheral edema, and a tricuspid regurgitation murmur.¹⁴ The prognosis of eosinophilic granuloma is variable. Although some patients progress to end-stage fibrotic lung disease requiring lung transplant, there have been reports of complete remission following cessation of cigarette smoking.¹⁷

Langerhans cells travel from the bone marrow to the epidermis where they express the CD1a protein on the surface of the antigen-presenting cell. Elevated levels of cytokines, such as tumor necrosis factor α, IFN-γ, granulocyte-macrophage colony-stimulating factor, and interleukins have been seen in patients with LCH.¹ Their role in the pathogenesis of this disease remains unknown, but the elevated levels of cytokines may indicate the lack of an efficient immune system.

Histologically, hematoxylin and eosin–stained sections demonstrate an infiltrate of histiocytes, neutrophils, eosinophils, and an increased number of mast cells involving the papillary and reticular dermis. Infiltrating Langerhans cells have concave reniform nuclei¹⁸ and stain positive for CD1a, S-100, and CD68 antigens.¹⁵ In 10% to 30% of CSHR cases, Birbeck granules can be seen on electron microscopy and tend to transform into laminated dense bodies, signifying the degenerative changes seen in CSHR.¹⁵ The various forms of LCH exhibit no significant differences in the expression of the epithelial cadherin, the phosphorylated histone H3, and the Ki-67 proteins, indicating that they are simply different forms of the same disease represented on a spectrum.¹⁵

Conclusion

The actual incidence of CSHR may be notably underreported due to its spontaneous regression and low rate of clinical recognition. A subtype of LCH, CSHR is a diagnosis of exclusion. Although CSHR generally follows a benign clinical course, a thorough workup and evaluation for systemic disease with close follow-up is recommended after diagnosis due to the potential of LCH to involve multiple organs and to relapse at a later date after apparent regression.

Langerhans cell histiocytosis (LCH), also known as histiocytosis X, is a general term that describes a group of rare disorders characterized by the proliferation of Langerhans cells.¹ Central to immune surveillance and the elimination of foreign substances from the body, Langerhans cells are derived from bone marrow progenitor cells and found in the epidermis but are capable of migrating from the skin to the lymph nodes. In LCH, these cells congregate on bone tissue, particularly in the head and neck region, causing a multitude of problems.²

The spectrum of LCH includes 4 variants: congenital self-healing reticulohistiocytosis (CSHR)(also known as Hashimoto-Pritzker disease), Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma (also known as pulmonary histiocytosis X)(Table). Despite the various clinical presentations and levels of severity, all variants are caused by the proliferation of Langerhans cells. We present a case of CSHR in a 6-month-old male infant that was initially diagnosed as molluscum contagiosum. We believe the actual incidence of CSHR may be underreported due to its spontaneous regression and low rate of clinical recognition.

Case Report

A 6-month-old male infant was referred to our clinic by his pediatrician with a generalized cutaneous eruption of 3 weeks’ duration. The eruption, which followed a recent viral upper respiratory tract infection, was characterized by multiple flesh-colored to erythematous, umbilicated papules distributed along the postauricular region, scalp (Figure 1A), abdomen (Figure 1B), and anterior aspect of the neck. Due to his recent illness, the patient was diagnosed with molluscum contagiosum by the referring pediatrician that was treated symptomatically with hydrocortisone lotion, Schamberg’s cream formulated in our office (a compound mixture of zinc oxide, menthol, calcium hydroxide solution, and olive oil), and pediatric diphenhydramine as needed. During a subsequent visit 2 weeks later, a more potent topical corticosteroid and a low-dose systemic corticosteroid was prescribed for 1 week due to development of new lesions and exacerbation of existing lesions. On follow-up 1 week later, the lesions on the trunk had improved, but the patient had developed new lesions on the scalp that differed from prior findings in that they were darker (more erythematous to brown) and firmer (papules and nodules).

Figure 1. Multiple fleshcolored to erythematous, umbilicated papules on the frontal scalp (A) and erythematous papules on the abdomen (B).

A shave biopsy was obtained from the frontal scalp to rule out LCH. Histologic examination and culture of the biopsy specimen revealed an atypical cellular infiltrate effacing the dermoepidermal junction and extensive epidermotropism. Focal erosion of the epidermis and an acute inflammatory exudate were visible. The nuclei of the cellular infiltrate were enlarged and hyperchromatic with a characteristic reniform appearance and indistinct nucleoli (Figure 2). The cells were admixed with scattered eosinophils and extravasated red blood cells.

Figure 2. Low-power view of dermal mononuclear cells with reniform nuclei (A)(H&E, original magnification ×100), and high-power view of enlarged and hyperchromatic nuclei with a characteristic reniform appearance admixed with eosinophils and extravasated red blood cells (B) (H&E, original magnification ×400).

Immunohistochemical staining of the biopsy specimen was strongly positive for both CD1a and S-100 expression (Figure 3). Histopathologic findings were consistent with LCH. Clinicopathologic correlation strongly favored the diagnosis of CSHR.

Comment

Congenital self-healing reticulohistiocytosis is a rare, benign, congenital variant of LCH that spontaneously resolves with no systemic involvement. The more aggressive forms typically manifest at birth or during the first 2 months of life and regress within 3 to 4 months.⁵ Since CSHR was first described in 1973 by Hashimoto and Pritzker,⁵ more than 100 cases have been reported, but the true incidence is believed to be higher than reported given the high rate of spontaneous resolution and the low rate of clinical recognition.² The first reported case of CSHR occurred in a female infant who presented at birth with multiple, diffusely distributed, red-brown papules that were 2 to 4 mm in diameter. Although the patient received no treatment, the exanthem completely resolved within 3.5 months without recurrence at 14-year follow-up.⁵ Most often, CSHR presents as multiple papules or nodules with occasional disseminated crusting and is followed within a few months by a dramatic and spontaneous regression. Lesions may heal with mild postinflammatory hyperpigmentation. Pseudo-Darier sign, the propensity to urticate from physical manipulation, has been reported in some lesions with an increased number of mast cells.⁶ Extensive superficial nasal and oral mucosal erosions have been reported in 2 cases.⁷ Solitary lesions have been reported in 25% of cases.⁸

The etiology of CSHR remains unknown, though neoplastic, viral, and immunologic origins have been suggested. There have been reports that human herpesvirus 6 may contribute to the development of LCH.⁹ It may be postulated that our patient’s presentation of CSHR was potentiated by his recent upper respiratory tract illness. In the literature, CSHR is distributed equally among males and females. Prevalence is higher in the white population than in other racial groups.⁵

Although CSHR is a benign cutaneous variant of LCH, there have been reports of patients with disseminated and extracutaneous involvement. In 1 rare case, CSHR reportedly involved the eyes, producing multiple, bilateral, well-circumscribed, diffuse, yellow-white lesions of the retinal pigment epithelium throughout the posterior pole of the eyes.¹⁰ The retinal lesions spontaneously regressed along with the skin manifestations. Additionally, it was reported that a neonate in Thailand presented with CSHR at birth and 1 month later developed multiple lung cysts that had completely regressed 11 months later.¹¹ One study reported that initial diagnoses of LCH in 18 patients with only cutaneous involvement eventually progressed to systemic LCH, requiring further management.¹² When LCH is suspected, a thorough physical examination, including hematologic and coagulation evaluation, liver function tests, musculoskeletal examination, and consultation with specialists if necessary, is recommended.¹³

There are 3 additional variants of LCH. Letterer-Siwe disease is an acute form of LCH that accounts for 10% of all LCH cases and typically presents in children younger than 2 years. It involves multiple organs, including the bones, lungs, liver, and lymph nodes.¹⁴ Affected patients usually present with fever; hepatosplenomegaly; anemia; lymphadenopathy; extensive lytic skull lesions; and a generalized cutaneous eruption, appearing as a maculopapular scaling rash with underlying purpura on the scalp, neck, axilla, and trunk.³ Letterer-Siwe disease is inherited in an autosomal-recessive pattern. Diagnosis is confirmed by skin biopsy demonstrating a thinning of the epidermis and a collection of reticulum cells in the dermis.³ Letterer-Siwe disease is treated with radiation and chemotherapy; if left untreated, the disease is fatal.⁴

Hand-Schüller-Christian disease, a chronic form of LCH, is most commonly seen in children aged 2 to 6 years and accounts for 15% to 20% of all LCH cases. This LCH variant presents with a classic triad of diabetes insipidus (resulting from erosion into the sella turcica), lytic bone lesions, and exophthalmos.¹⁵ Hand-Schüller-Christian disease also affects the oral cavity, producing nodular ulcerations of the hard palate, trouble swallowing, and halitosis.⁴ The involvement of lytic bone lesions of the mastoid process and petrous portions of the temporal bones may cause recurrent or chronic otitis media and otitis externa. Hand-Schüller-Christian disease is treated with a combination of chemotherapy, radiation, and surgical excision. The mortality rate is 30%.⁴

Eosinophilic granuloma is the most prevalent variant of LCH, accounting for 60% to 80% of all cases. Characterized by Langerhans cell granulomatous infiltration of the lungs and painful cystic bone lesions, eosinophilic granuloma primarily presents in the third or fourth decades of life.¹⁶ Some studies suggest an epidemiologic association with tobacco use.¹⁷ In the preliminary stages of this disease, Langerhans cells, eosinophils, lymphocytes, and fibroblasts infiltrate and form nodules on the terminal bronchioles in the upper and middle lung zones, damaging the airway walls.¹⁸ Fibrotic scarring progresses, ultimately resulting in alveolar destruction.¹⁰ The common signs and symptoms of eosinophilic granuloma are a nonproductive cough, dyspnea, weight loss, spontaneous pneumothorax, fever, peripheral edema, and a tricuspid regurgitation murmur.¹⁴ The prognosis of eosinophilic granuloma is variable. Although some patients progress to end-stage fibrotic lung disease requiring lung transplant, there have been reports of complete remission following cessation of cigarette smoking.¹⁷

Langerhans cells travel from the bone marrow to the epidermis where they express the CD1a protein on the surface of the antigen-presenting cell. Elevated levels of cytokines, such as tumor necrosis factor α, IFN-γ, granulocyte-macrophage colony-stimulating factor, and interleukins have been seen in patients with LCH.¹ Their role in the pathogenesis of this disease remains unknown, but the elevated levels of cytokines may indicate the lack of an efficient immune system.

Histologically, hematoxylin and eosin–stained sections demonstrate an infiltrate of histiocytes, neutrophils, eosinophils, and an increased number of mast cells involving the papillary and reticular dermis. Infiltrating Langerhans cells have concave reniform nuclei¹⁸ and stain positive for CD1a, S-100, and CD68 antigens.¹⁵ In 10% to 30% of CSHR cases, Birbeck granules can be seen on electron microscopy and tend to transform into laminated dense bodies, signifying the degenerative changes seen in CSHR.¹⁵ The various forms of LCH exhibit no significant differences in the expression of the epithelial cadherin, the phosphorylated histone H3, and the Ki-67 proteins, indicating that they are simply different forms of the same disease represented on a spectrum.¹⁵

Conclusion

The actual incidence of CSHR may be notably underreported due to its spontaneous regression and low rate of clinical recognition. A subtype of LCH, CSHR is a diagnosis of exclusion. Although CSHR generally follows a benign clinical course, a thorough workup and evaluation for systemic disease with close follow-up is recommended after diagnosis due to the potential of LCH to involve multiple organs and to relapse at a later date after apparent regression.

A 34-year-old African American woman presented to the emergency department (ED) after several hours of sharp lower abdominal pain and cramping followed by nausea and vomiting. The pain initially began in the periumbilical region and migrated to the bilateral lower quadrants. The patient reported no fevers, chills, diarrhea, hematemesis, or hematochezia associated with these symptoms. She also reported no unusual food exposures or sick contacts.

The patient’s medical history was notable only for hypertension; her surgical history included 2 cesarean section births several years prior to presentation. Her father was diagnosed with stomach cancer in his 40s. The patient’s only medications were an oral contraceptive, lisinopril, and an antihistamine taken as needed for seasonal allergies. She had no history of tobacco, alcohol, or illicit drug use and no known drug allergies.

While in the ED, the patient’s physical exam revealed mild tachycardia (104 bpm on arrival, which improved with fluid resuscitation) and diffuse abdominal tenderness. Laboratory evaluation revealed a mild leukocytosis (10.7 x 10³/L) but normal liver-associated enzymes, lipase, and urinalysis. A computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast revealed diffuse ileal wall thickening with significant perihepatic and perisplenic ascites with pelvic free fluid suspicious for an inflammatory vs infectious enteritis (Figure 1).

The patient was treated supportively with IV fluids, antiemetics, and pain medication. Her symptoms generally improved over several days, though she did develop loose stools that prompted infectious stool studies, which were negative for typical pathogens. Follow-up laboratory testing revealed resolution of her leukocytosis.

About 2 weeks later, the patient had another acute attack of abdominal pain, again associated with nausea and vomiting.

Six weeks after her initial presentation, the patient presented to the ED for the third time with the same symptoms. A CT scan again displayed diffuse ileal wall thickening with significant ascites; slightly worse than the image from initial presentation (Figure 3).
 

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Diagnosis

This patient presented with recurrent episodes of diffuse small bowel wall thickening and ascites associated with diffuse abdominal pain, nausea, and vomiting. Her symptoms resolved spontaneously, correlating with normalization of bowel wall appearance on imaging studies. Initially, the patient’s symptoms were most concerning for infectious or inflammatory enteritis. Infection became lower on the differential as the patient’s symptoms continued to recur and then resolve spontaneously without antiviral or antibiotic treatment. She also had no fevers, and stools samples were negative for infectious causes of her symptoms.

Inflammatory bowel disease (IBD) was considered, but direct visualization of the small bowel and colonic mucosa was unremarkable. In addition, the sporadic nature of her symptoms did not fit the typical IBD presentation. The patient had no risk factors or history that would suggest ischemic disease, vasculitis, or radiation-induced enteritis. Hereditary angioedema and acquired C1 esterase deficiency were considered given the intermittent nature and characteristic quality of her symptoms. However, serum C4 and C1 esterase inhibitor levels returned within normal limits when measured during these episodes. Finally, visceral angioedema was considered.

Visceral angioedema may be related to medications and is specifically associated with angiotensin-converting-enzyme (ACE) inhibitors as well as β-lactams and high doses of nonsteroidal anti-inflammatory drugs (NSAIDs). Given the characteristic presentation with no other inciting cause, the patient’s lisinopril was felt to be the causative agent and was discontinued. Her symptoms resolved completely and never returned. The patient’s final diagnosis was ACE inhibitor-induced visceral angioedema.

About This Condition

Angiotensin-converting enzyme inhibitors were first introduced in the early 1980s and have been prescribed more frequently as the indications for their use have increased. Some estimate that ACE inhibitors are used by more than 40 million people worldwide.¹ Angioedema has been reported to occur in 0.1% to 0.2% of patients taking ACE inhibitorsand accounts for 20% to 30% of all angioedema cases presenting to EDs.^2,3 However, ACE inhibitors recently have been recognized as a rare cause of angioedema of the gastrointestinal tract. One of the largest literature reviews on ACE inhibitor-induced gastrointestinal angioedema describes only 27 cases.³

Prevalence seems to be highest among middle-aged or older women, particularly among African Americans.³ The interval between medication initiation and onset of symptoms can vary, ranging from 24 hours to 9 years.^3,4 In many cases, lack of recognition of this condition early in the disease course led to costly and invasive procedures, such as abdominal laparotomy, before reaching a diagnosis. Other literature reviews report similar patient characteristics and initial disease manifestations: female predominance, often middle-aged, presenting with abdominal pain and emesis associated with bowel wall thickening and ascites on CT.^4,5 Additionally, in the majority of cases, visceral angioedema occurred in the absence of oropharyngeal angioedema. Unlike allergic angioedema or NSAID-induced angioedema, ACE inhibitor-induced angioedema is not associated with urticaria.⁶

The exact pathway of ACE inhibitor-induced angioedema is not completely understood but is thought to be bradykinin mediated. Angiotensin-converting enzyme inhibitors decrease the degradation of bradykinin, which ultimately leads to an increase in vascular permeability and results in an increased plasma extravasation into the interstitial space of subcutaneous or submucosal tissue.¹ However, many experts believe that the exclusive role of bradykinin is unlikely. Some suggest that patients with ACE inhibitor-induced angioedema are more likely to have decreased levels or defects in other enzymes such as carboxypeptidase N and aminopeptidase P, which are involved in the breakdown of bradykinin and its metabolites.⁶ Given the female predominance in this patient population, it also seems reasonable to consider the role of estrogens in the pathogenesis of this disease, although none have been identified to the knowledge of the authors.

Treatment of ACE inhibitor-induced angioedema is largely supportive following discontinuation of the offending medication. There have been case reports of infrequent, mild, recurrent episodes of angioedema, even after ACE inhibitor discontinuation, so these should be anticipated.⁷

Conclusions

Angiotensin-converting enzyme inhibitor-induced gastrointestinal angioedema is a rare condition. It generally presents as recurrent abdominal pain and nausea with CT findings of intestinal edema and ascites. It is more common among the middle-aged, women, and minorities. ACE inhibitor-induced angioedema should be kept on the differential for patients with the aforementioned characteristics, especially if infection, inflammatory bowel disease, ischemic disease, or vasculitis is deemed unlikely. Identifying this condition early can save patients from unnecessary hospitalizations, physical and emotional discomfort, and further health care costs.

A 34-year-old African American woman presented to the emergency department (ED) after several hours of sharp lower abdominal pain and cramping followed by nausea and vomiting. The pain initially began in the periumbilical region and migrated to the bilateral lower quadrants. The patient reported no fevers, chills, diarrhea, hematemesis, or hematochezia associated with these symptoms. She also reported no unusual food exposures or sick contacts.

The patient’s medical history was notable only for hypertension; her surgical history included 2 cesarean section births several years prior to presentation. Her father was diagnosed with stomach cancer in his 40s. The patient’s only medications were an oral contraceptive, lisinopril, and an antihistamine taken as needed for seasonal allergies. She had no history of tobacco, alcohol, or illicit drug use and no known drug allergies.

While in the ED, the patient’s physical exam revealed mild tachycardia (104 bpm on arrival, which improved with fluid resuscitation) and diffuse abdominal tenderness. Laboratory evaluation revealed a mild leukocytosis (10.7 x 10³/L) but normal liver-associated enzymes, lipase, and urinalysis. A computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast revealed diffuse ileal wall thickening with significant perihepatic and perisplenic ascites with pelvic free fluid suspicious for an inflammatory vs infectious enteritis (Figure 1).

The patient was treated supportively with IV fluids, antiemetics, and pain medication. Her symptoms generally improved over several days, though she did develop loose stools that prompted infectious stool studies, which were negative for typical pathogens. Follow-up laboratory testing revealed resolution of her leukocytosis.

About 2 weeks later, the patient had another acute attack of abdominal pain, again associated with nausea and vomiting.

Six weeks after her initial presentation, the patient presented to the ED for the third time with the same symptoms. A CT scan again displayed diffuse ileal wall thickening with significant ascites; slightly worse than the image from initial presentation (Figure 3).
 

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Diagnosis

This patient presented with recurrent episodes of diffuse small bowel wall thickening and ascites associated with diffuse abdominal pain, nausea, and vomiting. Her symptoms resolved spontaneously, correlating with normalization of bowel wall appearance on imaging studies. Initially, the patient’s symptoms were most concerning for infectious or inflammatory enteritis. Infection became lower on the differential as the patient’s symptoms continued to recur and then resolve spontaneously without antiviral or antibiotic treatment. She also had no fevers, and stools samples were negative for infectious causes of her symptoms.

Inflammatory bowel disease (IBD) was considered, but direct visualization of the small bowel and colonic mucosa was unremarkable. In addition, the sporadic nature of her symptoms did not fit the typical IBD presentation. The patient had no risk factors or history that would suggest ischemic disease, vasculitis, or radiation-induced enteritis. Hereditary angioedema and acquired C1 esterase deficiency were considered given the intermittent nature and characteristic quality of her symptoms. However, serum C4 and C1 esterase inhibitor levels returned within normal limits when measured during these episodes. Finally, visceral angioedema was considered.

Visceral angioedema may be related to medications and is specifically associated with angiotensin-converting-enzyme (ACE) inhibitors as well as β-lactams and high doses of nonsteroidal anti-inflammatory drugs (NSAIDs). Given the characteristic presentation with no other inciting cause, the patient’s lisinopril was felt to be the causative agent and was discontinued. Her symptoms resolved completely and never returned. The patient’s final diagnosis was ACE inhibitor-induced visceral angioedema.

About This Condition

Angiotensin-converting enzyme inhibitors were first introduced in the early 1980s and have been prescribed more frequently as the indications for their use have increased. Some estimate that ACE inhibitors are used by more than 40 million people worldwide.¹ Angioedema has been reported to occur in 0.1% to 0.2% of patients taking ACE inhibitorsand accounts for 20% to 30% of all angioedema cases presenting to EDs.^2,3 However, ACE inhibitors recently have been recognized as a rare cause of angioedema of the gastrointestinal tract. One of the largest literature reviews on ACE inhibitor-induced gastrointestinal angioedema describes only 27 cases.³

Prevalence seems to be highest among middle-aged or older women, particularly among African Americans.³ The interval between medication initiation and onset of symptoms can vary, ranging from 24 hours to 9 years.^3,4 In many cases, lack of recognition of this condition early in the disease course led to costly and invasive procedures, such as abdominal laparotomy, before reaching a diagnosis. Other literature reviews report similar patient characteristics and initial disease manifestations: female predominance, often middle-aged, presenting with abdominal pain and emesis associated with bowel wall thickening and ascites on CT.^4,5 Additionally, in the majority of cases, visceral angioedema occurred in the absence of oropharyngeal angioedema. Unlike allergic angioedema or NSAID-induced angioedema, ACE inhibitor-induced angioedema is not associated with urticaria.⁶

The exact pathway of ACE inhibitor-induced angioedema is not completely understood but is thought to be bradykinin mediated. Angiotensin-converting enzyme inhibitors decrease the degradation of bradykinin, which ultimately leads to an increase in vascular permeability and results in an increased plasma extravasation into the interstitial space of subcutaneous or submucosal tissue.¹ However, many experts believe that the exclusive role of bradykinin is unlikely. Some suggest that patients with ACE inhibitor-induced angioedema are more likely to have decreased levels or defects in other enzymes such as carboxypeptidase N and aminopeptidase P, which are involved in the breakdown of bradykinin and its metabolites.⁶ Given the female predominance in this patient population, it also seems reasonable to consider the role of estrogens in the pathogenesis of this disease, although none have been identified to the knowledge of the authors.

Treatment of ACE inhibitor-induced angioedema is largely supportive following discontinuation of the offending medication. There have been case reports of infrequent, mild, recurrent episodes of angioedema, even after ACE inhibitor discontinuation, so these should be anticipated.⁷

Conclusions

Angiotensin-converting enzyme inhibitor-induced gastrointestinal angioedema is a rare condition. It generally presents as recurrent abdominal pain and nausea with CT findings of intestinal edema and ascites. It is more common among the middle-aged, women, and minorities. ACE inhibitor-induced angioedema should be kept on the differential for patients with the aforementioned characteristics, especially if infection, inflammatory bowel disease, ischemic disease, or vasculitis is deemed unlikely. Identifying this condition early can save patients from unnecessary hospitalizations, physical and emotional discomfort, and further health care costs.

A 34-year-old African American woman presented to the emergency department (ED) after several hours of sharp lower abdominal pain and cramping followed by nausea and vomiting. The pain initially began in the periumbilical region and migrated to the bilateral lower quadrants. The patient reported no fevers, chills, diarrhea, hematemesis, or hematochezia associated with these symptoms. She also reported no unusual food exposures or sick contacts.

The patient’s medical history was notable only for hypertension; her surgical history included 2 cesarean section births several years prior to presentation. Her father was diagnosed with stomach cancer in his 40s. The patient’s only medications were an oral contraceptive, lisinopril, and an antihistamine taken as needed for seasonal allergies. She had no history of tobacco, alcohol, or illicit drug use and no known drug allergies.

While in the ED, the patient’s physical exam revealed mild tachycardia (104 bpm on arrival, which improved with fluid resuscitation) and diffuse abdominal tenderness. Laboratory evaluation revealed a mild leukocytosis (10.7 x 10³/L) but normal liver-associated enzymes, lipase, and urinalysis. A computed tomography (CT) scan of the abdomen and pelvis with oral and IV contrast revealed diffuse ileal wall thickening with significant perihepatic and perisplenic ascites with pelvic free fluid suspicious for an inflammatory vs infectious enteritis (Figure 1).

The patient was treated supportively with IV fluids, antiemetics, and pain medication. Her symptoms generally improved over several days, though she did develop loose stools that prompted infectious stool studies, which were negative for typical pathogens. Follow-up laboratory testing revealed resolution of her leukocytosis.

About 2 weeks later, the patient had another acute attack of abdominal pain, again associated with nausea and vomiting.

Six weeks after her initial presentation, the patient presented to the ED for the third time with the same symptoms. A CT scan again displayed diffuse ileal wall thickening with significant ascites; slightly worse than the image from initial presentation (Figure 3).
 

• What is your diagnosis?
• How would you treat this patient? 

[Click through to the next page to see the answer.]

Diagnosis

This patient presented with recurrent episodes of diffuse small bowel wall thickening and ascites associated with diffuse abdominal pain, nausea, and vomiting. Her symptoms resolved spontaneously, correlating with normalization of bowel wall appearance on imaging studies. Initially, the patient’s symptoms were most concerning for infectious or inflammatory enteritis. Infection became lower on the differential as the patient’s symptoms continued to recur and then resolve spontaneously without antiviral or antibiotic treatment. She also had no fevers, and stools samples were negative for infectious causes of her symptoms.

Inflammatory bowel disease (IBD) was considered, but direct visualization of the small bowel and colonic mucosa was unremarkable. In addition, the sporadic nature of her symptoms did not fit the typical IBD presentation. The patient had no risk factors or history that would suggest ischemic disease, vasculitis, or radiation-induced enteritis. Hereditary angioedema and acquired C1 esterase deficiency were considered given the intermittent nature and characteristic quality of her symptoms. However, serum C4 and C1 esterase inhibitor levels returned within normal limits when measured during these episodes. Finally, visceral angioedema was considered.

Visceral angioedema may be related to medications and is specifically associated with angiotensin-converting-enzyme (ACE) inhibitors as well as β-lactams and high doses of nonsteroidal anti-inflammatory drugs (NSAIDs). Given the characteristic presentation with no other inciting cause, the patient’s lisinopril was felt to be the causative agent and was discontinued. Her symptoms resolved completely and never returned. The patient’s final diagnosis was ACE inhibitor-induced visceral angioedema.

About This Condition

Angiotensin-converting enzyme inhibitors were first introduced in the early 1980s and have been prescribed more frequently as the indications for their use have increased. Some estimate that ACE inhibitors are used by more than 40 million people worldwide.¹ Angioedema has been reported to occur in 0.1% to 0.2% of patients taking ACE inhibitorsand accounts for 20% to 30% of all angioedema cases presenting to EDs.^2,3 However, ACE inhibitors recently have been recognized as a rare cause of angioedema of the gastrointestinal tract. One of the largest literature reviews on ACE inhibitor-induced gastrointestinal angioedema describes only 27 cases.³

Prevalence seems to be highest among middle-aged or older women, particularly among African Americans.³ The interval between medication initiation and onset of symptoms can vary, ranging from 24 hours to 9 years.^3,4 In many cases, lack of recognition of this condition early in the disease course led to costly and invasive procedures, such as abdominal laparotomy, before reaching a diagnosis. Other literature reviews report similar patient characteristics and initial disease manifestations: female predominance, often middle-aged, presenting with abdominal pain and emesis associated with bowel wall thickening and ascites on CT.^4,5 Additionally, in the majority of cases, visceral angioedema occurred in the absence of oropharyngeal angioedema. Unlike allergic angioedema or NSAID-induced angioedema, ACE inhibitor-induced angioedema is not associated with urticaria.⁶

The exact pathway of ACE inhibitor-induced angioedema is not completely understood but is thought to be bradykinin mediated. Angiotensin-converting enzyme inhibitors decrease the degradation of bradykinin, which ultimately leads to an increase in vascular permeability and results in an increased plasma extravasation into the interstitial space of subcutaneous or submucosal tissue.¹ However, many experts believe that the exclusive role of bradykinin is unlikely. Some suggest that patients with ACE inhibitor-induced angioedema are more likely to have decreased levels or defects in other enzymes such as carboxypeptidase N and aminopeptidase P, which are involved in the breakdown of bradykinin and its metabolites.⁶ Given the female predominance in this patient population, it also seems reasonable to consider the role of estrogens in the pathogenesis of this disease, although none have been identified to the knowledge of the authors.

Treatment of ACE inhibitor-induced angioedema is largely supportive following discontinuation of the offending medication. There have been case reports of infrequent, mild, recurrent episodes of angioedema, even after ACE inhibitor discontinuation, so these should be anticipated.⁷

Conclusions

Angiotensin-converting enzyme inhibitor-induced gastrointestinal angioedema is a rare condition. It generally presents as recurrent abdominal pain and nausea with CT findings of intestinal edema and ascites. It is more common among the middle-aged, women, and minorities. ACE inhibitor-induced angioedema should be kept on the differential for patients with the aforementioned characteristics, especially if infection, inflammatory bowel disease, ischemic disease, or vasculitis is deemed unlikely. Identifying this condition early can save patients from unnecessary hospitalizations, physical and emotional discomfort, and further health care costs.

The emergence of hepatitis C (HCV) treatment regimens in the past 5 years has resulted in a major paradigm shift in the management of those infected with this virus. The 2011 approval of boceprevir and telaprevir was associated with a higher virologic response (50%-75%) and a shorter length of therapy depending on the patient population. Despite these gains, first generation direct-acting antivirals (DAAs) required multiple doses, had a higher pill burden with numerous drug interactions, and adverse effects (AEs). In addition, viral resistance limited the full use of the first generation DAAs for all genotypes.

Sofosbuvir, simeprevir, and ledipasvir-sofosbuvir (second generation DAAs) boast even higher (> 90%) sustained virologic response rates (SVR) and more tolerable AE profiles especially anemia, depression, and gastrointestinal symptoms compared with the first generation DAAs. At the time of treatment for this case study, sofosbuvir/ledipasvir was not commercially available. Sofosbuvir in combination with simeprevir with or without ribavirin was one of the preferred treatment options for chronic HCV.¹

Unlike the first generation DAAs, which have been associated with a decline in renal function compared with conventional pegylated interferon and ribavirin, sofosbuvir is extensively renally eliminated by glomerular filtration and active tubular secretion as the metabolite GS-331007. On the other hand, simeprevir is hepatically metabolized.

A PubMed literature search for reports of “simeprevir-induced” or “sofosbuvir-induced with hepatic, renal failure, acute kidney injury” yielded only 1 published case of hepatic decompensation likely related to simeprevir, but no case report of simeprevir and sofosbuvir associated with hepatic decompensation and acute kidney injury.⁴ In this article, the authors describe a case of hepatic decompensation and acute kidney injury caused by simeprevir/sofosbuvir initiation for chronic HCV that required intensive care and dialysis.

Case Report

The patient was a 62-year-old African American man with chronic HCV, genotype 1b, TT IL28B, and 4,980,000 IU baseline viral load. He was treatment naïve with biopsy proven compensated cirrhosis, and Child-Turcotte-Pugh class A with a pretreatment model for end-stage liver disease score of 12. His past medical history included hypertension, chronic kidney disease (CKD) (baseline serum creatinine [SCr] 1.4-1.8 mg/dL), benign prostatic hypertrophy, depression, obesity (30.6 body mass index, 246 lb), and psoriasis. In addition, the patient was on the following maintenance medications: allopurinol, bupropion, diltiazem, sustained-release and immediate-release morphine, sennosides, and terazosin.

In September 2014, the patient was diagnosed with biopsy-confirmed hepatocellular carcinoma (HCC) Barcelona clinic liver cancer stage B T3aN0M0 stage III. He was considered for transarterial chemoembolization (TACE), but treatment was withheld due to subsequent increase in liver function tests (LFTs) with total bilirubin (TB) 2.9 mg/dL, direct bilirubin (DB) 1.8 mg/dL, aspartate aminotransferase test (AST) 130 U/L, and alanine aminotransferase test (ALT) 188 U/L (baseline: TB 1.1 mg/dL, AST 69 U/L, and ALT 76 U/L). These results were thought to be the result of worsening hepatic function from untreated HCV, therefore, treatment was initiated.

The patient was started on simeprevir 150 mg orally daily and sofosbuvir 400 mg orally daily with an estimated baseline creatinine clearance of 67 mL/min per Cockcroft-Gault equation.⁵ Two days after therapy initiation, the patient presented to the emergency department with the following symptoms: hiccups, nausea, vomiting, and abdominal pain. Laboratory results showed 10.85 mg/dL SCr and 91 mg/dL blood urea nitrogen (BUN), TB increased to 14.6 mg/dL with AST of 325 U/L and ALT 277 U/L. The patient reported no use of acetaminophen, alcohol, nonsteroidal anti-inflammatory drugs, or other nephrotoxic agents.

Upon admission, the patient was diagnosed with drug-induced hepatitis and acute kidney injury (AKI). Simeprevir/sofosbuvir was discontinued along with allopurinol, bupropion, lisinopril, and morphine. An abdominal ultrasound was negative for obstructive uropathy. The patient did not respond to fluid boluses. A nephrologist was consulted, and dialysis was initiated. The patient underwent dialysis for 3 days and his LFTs and SCr levels started trending downward (Figures 1 to 5).

The patient was discharged after 8 days. After 3 weeks, the SCr decreased to 2.29 mg/dL, BUN was 26 mg/dL, TB was 2 mg/dL, DB was 0.9 mg/dL, AST was 73 U/L, and ALT was 81 U/L. Weekly laboratory values continued to improve following discharge but did not return to baseline levels. The patient remained off HCV treatment.

Discussion

The patient had baseline CKD with SCr > 1.5 mg/dL; however, the significant decline in renal function and worsening hepatic function were thought to be the result of external factors. Although hepatorenal syndrome was considered, the authors suspected that the AKI and hepatic decompensation were related to simeprevir/sofosbuvir regimens due to their presumed relationship and probability analysis. Osinusi and colleagues noted a decline in renal function in a patient who received ledipasvir/sofosbuvir for 6 weeks in an open-label pilot study.⁶ Stine and colleagues also reported on cases of simeprevir-related hepatic decompensation.⁴

In this case, the authors employed the Naranjo algorithm adverse drug reaction probability scale to assess whether there was a causal relationship between this event and initiation of simeprevir/sofosbuvir regimen.⁷ The Naranjo score was 4, indicating a possible link between simeprevir/sofosbuvir initiation and hepatic decompensation and AKI. This case may be the first postmarketing report of significant hepatic decompensation and AKI related to simeprevir/sofosbuvir.

Unlike simeprevir, which undergoes extensive oxidative metabolism by CYP3A in the liver and has negligible renal clearance with < 1% of the dose recovered in the urine, sofosbuvir is extensively metabolized by the kidneys with an active metabolite, GS-331007, and about 80% of the dose is recovered in urine (78% as GS-331007; 3.5% as sofosbuvir).^8,9 The potential for drug-drug interaction also was assessed because simeprevir is extensively metabolized by the hepatic cytochrome CYP34 system and possibly CYP2C8 and CYP2C19. Clinically significant interactions could have occurred with diltiazem and morphine, because the coadministration of these medications along with simeprevir, an inhibitor of P-glycoprotein (P-gp), and intestinal CYP3A4, may result in increased diltiazem and morphine plasma concentrations.

Of note, because sofosbuvir is a substrate of P-gp, it may have its serum concentration increased by simeprevir. Inducers and inhibitors of P-gp may alter the plasma concentration of sofosbuvir. The major metabolite, GS-331007, is not a substrate of P-gp. Drugs that induce P-gp may reduce the therapeutic effect of sofosbuvir; however, the FDA-labeling suggests that inhibitors of P-gp may be coadministered with sofosbuvir.

According to simeprevir prescribing information, drug interaction studies have demonstrated that moderate CYP3A4 inhibitors, such as diltiazem (although coadministration have not been studied), increased the maximum serum concentration (C_max), minumum serum concentration (C_min), and AUC of simeprevir.⁷ As a result, concurrent use of simeprevir with a moderate CYP3A4 inhibitors is not recommended. Morphine and simeprevir interaction also is possible via the P-gp inhibition of simeprevir. Morphine concentration may have increased and metabolites may have accumulated, leading to urinary retention and elevated creatinine. In addition, decreased oral intake and subsequent nausea/vomiting may have compounded the renal insult.

Conclusion

Given that updated HCV treatment guidelines include simeprevir/sofosbuvir as an alternative treatment option, clinicians should be aware of hepatic decompensation with markedly elevated bilirubin and AKI during simeprevir and sofosbuvir treatment. Careful consideration is needed prior to the initiation of simeprevir/sofosbuvir, particularly in patients with advanced liver disease or known HCC and baseline renal impairment.

The emergence of hepatitis C (HCV) treatment regimens in the past 5 years has resulted in a major paradigm shift in the management of those infected with this virus. The 2011 approval of boceprevir and telaprevir was associated with a higher virologic response (50%-75%) and a shorter length of therapy depending on the patient population. Despite these gains, first generation direct-acting antivirals (DAAs) required multiple doses, had a higher pill burden with numerous drug interactions, and adverse effects (AEs). In addition, viral resistance limited the full use of the first generation DAAs for all genotypes.

Sofosbuvir, simeprevir, and ledipasvir-sofosbuvir (second generation DAAs) boast even higher (> 90%) sustained virologic response rates (SVR) and more tolerable AE profiles especially anemia, depression, and gastrointestinal symptoms compared with the first generation DAAs. At the time of treatment for this case study, sofosbuvir/ledipasvir was not commercially available. Sofosbuvir in combination with simeprevir with or without ribavirin was one of the preferred treatment options for chronic HCV.¹

Unlike the first generation DAAs, which have been associated with a decline in renal function compared with conventional pegylated interferon and ribavirin, sofosbuvir is extensively renally eliminated by glomerular filtration and active tubular secretion as the metabolite GS-331007. On the other hand, simeprevir is hepatically metabolized.

A PubMed literature search for reports of “simeprevir-induced” or “sofosbuvir-induced with hepatic, renal failure, acute kidney injury” yielded only 1 published case of hepatic decompensation likely related to simeprevir, but no case report of simeprevir and sofosbuvir associated with hepatic decompensation and acute kidney injury.⁴ In this article, the authors describe a case of hepatic decompensation and acute kidney injury caused by simeprevir/sofosbuvir initiation for chronic HCV that required intensive care and dialysis.

Case Report

The patient was a 62-year-old African American man with chronic HCV, genotype 1b, TT IL28B, and 4,980,000 IU baseline viral load. He was treatment naïve with biopsy proven compensated cirrhosis, and Child-Turcotte-Pugh class A with a pretreatment model for end-stage liver disease score of 12. His past medical history included hypertension, chronic kidney disease (CKD) (baseline serum creatinine [SCr] 1.4-1.8 mg/dL), benign prostatic hypertrophy, depression, obesity (30.6 body mass index, 246 lb), and psoriasis. In addition, the patient was on the following maintenance medications: allopurinol, bupropion, diltiazem, sustained-release and immediate-release morphine, sennosides, and terazosin.

In September 2014, the patient was diagnosed with biopsy-confirmed hepatocellular carcinoma (HCC) Barcelona clinic liver cancer stage B T3aN0M0 stage III. He was considered for transarterial chemoembolization (TACE), but treatment was withheld due to subsequent increase in liver function tests (LFTs) with total bilirubin (TB) 2.9 mg/dL, direct bilirubin (DB) 1.8 mg/dL, aspartate aminotransferase test (AST) 130 U/L, and alanine aminotransferase test (ALT) 188 U/L (baseline: TB 1.1 mg/dL, AST 69 U/L, and ALT 76 U/L). These results were thought to be the result of worsening hepatic function from untreated HCV, therefore, treatment was initiated.

The patient was started on simeprevir 150 mg orally daily and sofosbuvir 400 mg orally daily with an estimated baseline creatinine clearance of 67 mL/min per Cockcroft-Gault equation.⁵ Two days after therapy initiation, the patient presented to the emergency department with the following symptoms: hiccups, nausea, vomiting, and abdominal pain. Laboratory results showed 10.85 mg/dL SCr and 91 mg/dL blood urea nitrogen (BUN), TB increased to 14.6 mg/dL with AST of 325 U/L and ALT 277 U/L. The patient reported no use of acetaminophen, alcohol, nonsteroidal anti-inflammatory drugs, or other nephrotoxic agents.

Upon admission, the patient was diagnosed with drug-induced hepatitis and acute kidney injury (AKI). Simeprevir/sofosbuvir was discontinued along with allopurinol, bupropion, lisinopril, and morphine. An abdominal ultrasound was negative for obstructive uropathy. The patient did not respond to fluid boluses. A nephrologist was consulted, and dialysis was initiated. The patient underwent dialysis for 3 days and his LFTs and SCr levels started trending downward (Figures 1 to 5).

The patient was discharged after 8 days. After 3 weeks, the SCr decreased to 2.29 mg/dL, BUN was 26 mg/dL, TB was 2 mg/dL, DB was 0.9 mg/dL, AST was 73 U/L, and ALT was 81 U/L. Weekly laboratory values continued to improve following discharge but did not return to baseline levels. The patient remained off HCV treatment.

Discussion

The patient had baseline CKD with SCr > 1.5 mg/dL; however, the significant decline in renal function and worsening hepatic function were thought to be the result of external factors. Although hepatorenal syndrome was considered, the authors suspected that the AKI and hepatic decompensation were related to simeprevir/sofosbuvir regimens due to their presumed relationship and probability analysis. Osinusi and colleagues noted a decline in renal function in a patient who received ledipasvir/sofosbuvir for 6 weeks in an open-label pilot study.⁶ Stine and colleagues also reported on cases of simeprevir-related hepatic decompensation.⁴

In this case, the authors employed the Naranjo algorithm adverse drug reaction probability scale to assess whether there was a causal relationship between this event and initiation of simeprevir/sofosbuvir regimen.⁷ The Naranjo score was 4, indicating a possible link between simeprevir/sofosbuvir initiation and hepatic decompensation and AKI. This case may be the first postmarketing report of significant hepatic decompensation and AKI related to simeprevir/sofosbuvir.

Unlike simeprevir, which undergoes extensive oxidative metabolism by CYP3A in the liver and has negligible renal clearance with < 1% of the dose recovered in the urine, sofosbuvir is extensively metabolized by the kidneys with an active metabolite, GS-331007, and about 80% of the dose is recovered in urine (78% as GS-331007; 3.5% as sofosbuvir).^8,9 The potential for drug-drug interaction also was assessed because simeprevir is extensively metabolized by the hepatic cytochrome CYP34 system and possibly CYP2C8 and CYP2C19. Clinically significant interactions could have occurred with diltiazem and morphine, because the coadministration of these medications along with simeprevir, an inhibitor of P-glycoprotein (P-gp), and intestinal CYP3A4, may result in increased diltiazem and morphine plasma concentrations.

Of note, because sofosbuvir is a substrate of P-gp, it may have its serum concentration increased by simeprevir. Inducers and inhibitors of P-gp may alter the plasma concentration of sofosbuvir. The major metabolite, GS-331007, is not a substrate of P-gp. Drugs that induce P-gp may reduce the therapeutic effect of sofosbuvir; however, the FDA-labeling suggests that inhibitors of P-gp may be coadministered with sofosbuvir.

According to simeprevir prescribing information, drug interaction studies have demonstrated that moderate CYP3A4 inhibitors, such as diltiazem (although coadministration have not been studied), increased the maximum serum concentration (C_max), minumum serum concentration (C_min), and AUC of simeprevir.⁷ As a result, concurrent use of simeprevir with a moderate CYP3A4 inhibitors is not recommended. Morphine and simeprevir interaction also is possible via the P-gp inhibition of simeprevir. Morphine concentration may have increased and metabolites may have accumulated, leading to urinary retention and elevated creatinine. In addition, decreased oral intake and subsequent nausea/vomiting may have compounded the renal insult.

Conclusion

Given that updated HCV treatment guidelines include simeprevir/sofosbuvir as an alternative treatment option, clinicians should be aware of hepatic decompensation with markedly elevated bilirubin and AKI during simeprevir and sofosbuvir treatment. Careful consideration is needed prior to the initiation of simeprevir/sofosbuvir, particularly in patients with advanced liver disease or known HCC and baseline renal impairment.

The emergence of hepatitis C (HCV) treatment regimens in the past 5 years has resulted in a major paradigm shift in the management of those infected with this virus. The 2011 approval of boceprevir and telaprevir was associated with a higher virologic response (50%-75%) and a shorter length of therapy depending on the patient population. Despite these gains, first generation direct-acting antivirals (DAAs) required multiple doses, had a higher pill burden with numerous drug interactions, and adverse effects (AEs). In addition, viral resistance limited the full use of the first generation DAAs for all genotypes.

Sofosbuvir, simeprevir, and ledipasvir-sofosbuvir (second generation DAAs) boast even higher (> 90%) sustained virologic response rates (SVR) and more tolerable AE profiles especially anemia, depression, and gastrointestinal symptoms compared with the first generation DAAs. At the time of treatment for this case study, sofosbuvir/ledipasvir was not commercially available. Sofosbuvir in combination with simeprevir with or without ribavirin was one of the preferred treatment options for chronic HCV.¹

Unlike the first generation DAAs, which have been associated with a decline in renal function compared with conventional pegylated interferon and ribavirin, sofosbuvir is extensively renally eliminated by glomerular filtration and active tubular secretion as the metabolite GS-331007. On the other hand, simeprevir is hepatically metabolized.

A PubMed literature search for reports of “simeprevir-induced” or “sofosbuvir-induced with hepatic, renal failure, acute kidney injury” yielded only 1 published case of hepatic decompensation likely related to simeprevir, but no case report of simeprevir and sofosbuvir associated with hepatic decompensation and acute kidney injury.⁴ In this article, the authors describe a case of hepatic decompensation and acute kidney injury caused by simeprevir/sofosbuvir initiation for chronic HCV that required intensive care and dialysis.

Case Report

The patient was a 62-year-old African American man with chronic HCV, genotype 1b, TT IL28B, and 4,980,000 IU baseline viral load. He was treatment naïve with biopsy proven compensated cirrhosis, and Child-Turcotte-Pugh class A with a pretreatment model for end-stage liver disease score of 12. His past medical history included hypertension, chronic kidney disease (CKD) (baseline serum creatinine [SCr] 1.4-1.8 mg/dL), benign prostatic hypertrophy, depression, obesity (30.6 body mass index, 246 lb), and psoriasis. In addition, the patient was on the following maintenance medications: allopurinol, bupropion, diltiazem, sustained-release and immediate-release morphine, sennosides, and terazosin.

In September 2014, the patient was diagnosed with biopsy-confirmed hepatocellular carcinoma (HCC) Barcelona clinic liver cancer stage B T3aN0M0 stage III. He was considered for transarterial chemoembolization (TACE), but treatment was withheld due to subsequent increase in liver function tests (LFTs) with total bilirubin (TB) 2.9 mg/dL, direct bilirubin (DB) 1.8 mg/dL, aspartate aminotransferase test (AST) 130 U/L, and alanine aminotransferase test (ALT) 188 U/L (baseline: TB 1.1 mg/dL, AST 69 U/L, and ALT 76 U/L). These results were thought to be the result of worsening hepatic function from untreated HCV, therefore, treatment was initiated.

The patient was started on simeprevir 150 mg orally daily and sofosbuvir 400 mg orally daily with an estimated baseline creatinine clearance of 67 mL/min per Cockcroft-Gault equation.⁵ Two days after therapy initiation, the patient presented to the emergency department with the following symptoms: hiccups, nausea, vomiting, and abdominal pain. Laboratory results showed 10.85 mg/dL SCr and 91 mg/dL blood urea nitrogen (BUN), TB increased to 14.6 mg/dL with AST of 325 U/L and ALT 277 U/L. The patient reported no use of acetaminophen, alcohol, nonsteroidal anti-inflammatory drugs, or other nephrotoxic agents.

Upon admission, the patient was diagnosed with drug-induced hepatitis and acute kidney injury (AKI). Simeprevir/sofosbuvir was discontinued along with allopurinol, bupropion, lisinopril, and morphine. An abdominal ultrasound was negative for obstructive uropathy. The patient did not respond to fluid boluses. A nephrologist was consulted, and dialysis was initiated. The patient underwent dialysis for 3 days and his LFTs and SCr levels started trending downward (Figures 1 to 5).

The patient was discharged after 8 days. After 3 weeks, the SCr decreased to 2.29 mg/dL, BUN was 26 mg/dL, TB was 2 mg/dL, DB was 0.9 mg/dL, AST was 73 U/L, and ALT was 81 U/L. Weekly laboratory values continued to improve following discharge but did not return to baseline levels. The patient remained off HCV treatment.

Discussion

The patient had baseline CKD with SCr > 1.5 mg/dL; however, the significant decline in renal function and worsening hepatic function were thought to be the result of external factors. Although hepatorenal syndrome was considered, the authors suspected that the AKI and hepatic decompensation were related to simeprevir/sofosbuvir regimens due to their presumed relationship and probability analysis. Osinusi and colleagues noted a decline in renal function in a patient who received ledipasvir/sofosbuvir for 6 weeks in an open-label pilot study.⁶ Stine and colleagues also reported on cases of simeprevir-related hepatic decompensation.⁴

In this case, the authors employed the Naranjo algorithm adverse drug reaction probability scale to assess whether there was a causal relationship between this event and initiation of simeprevir/sofosbuvir regimen.⁷ The Naranjo score was 4, indicating a possible link between simeprevir/sofosbuvir initiation and hepatic decompensation and AKI. This case may be the first postmarketing report of significant hepatic decompensation and AKI related to simeprevir/sofosbuvir.

Unlike simeprevir, which undergoes extensive oxidative metabolism by CYP3A in the liver and has negligible renal clearance with < 1% of the dose recovered in the urine, sofosbuvir is extensively metabolized by the kidneys with an active metabolite, GS-331007, and about 80% of the dose is recovered in urine (78% as GS-331007; 3.5% as sofosbuvir).^8,9 The potential for drug-drug interaction also was assessed because simeprevir is extensively metabolized by the hepatic cytochrome CYP34 system and possibly CYP2C8 and CYP2C19. Clinically significant interactions could have occurred with diltiazem and morphine, because the coadministration of these medications along with simeprevir, an inhibitor of P-glycoprotein (P-gp), and intestinal CYP3A4, may result in increased diltiazem and morphine plasma concentrations.

Of note, because sofosbuvir is a substrate of P-gp, it may have its serum concentration increased by simeprevir. Inducers and inhibitors of P-gp may alter the plasma concentration of sofosbuvir. The major metabolite, GS-331007, is not a substrate of P-gp. Drugs that induce P-gp may reduce the therapeutic effect of sofosbuvir; however, the FDA-labeling suggests that inhibitors of P-gp may be coadministered with sofosbuvir.

According to simeprevir prescribing information, drug interaction studies have demonstrated that moderate CYP3A4 inhibitors, such as diltiazem (although coadministration have not been studied), increased the maximum serum concentration (C_max), minumum serum concentration (C_min), and AUC of simeprevir.⁷ As a result, concurrent use of simeprevir with a moderate CYP3A4 inhibitors is not recommended. Morphine and simeprevir interaction also is possible via the P-gp inhibition of simeprevir. Morphine concentration may have increased and metabolites may have accumulated, leading to urinary retention and elevated creatinine. In addition, decreased oral intake and subsequent nausea/vomiting may have compounded the renal insult.

Conclusion

Given that updated HCV treatment guidelines include simeprevir/sofosbuvir as an alternative treatment option, clinicians should be aware of hepatic decompensation with markedly elevated bilirubin and AKI during simeprevir and sofosbuvir treatment. Careful consideration is needed prior to the initiation of simeprevir/sofosbuvir, particularly in patients with advanced liver disease or known HCC and baseline renal impairment.

The use of thrombolytic medications for the treatment of acute ischemic cerebral infarctions has dynamically altered stroke care. However, there are both major and minor side effects associated with its use—most notably major bleeding, which led to strict inclusion and exclusion criteria governing the administration of this medication class. One less recognized but potentially serious complication is angioedema secondary to tissue plasminogen activator (tPA). Our case emphasizes the importance of early recognition of this clinical syndrome as it relates to airway compromise and potential respiratory failure in patients who are treated with tPA.

Case

A 70-year-old woman with a history of diabetes and hypertension and a remote history of breast cancer, nonhemiplegic migraines, and hypothyroidism presented to the ED with complaints of aphasia and right-sided paralysis, with onset 2 hours prior. Regarding the patient’s medication history, she had been taking lisinopril for hypertension.

Upon assessment, the patient was awake and alert and her vital signs were normal and stable, but she was aphasic, unable to accurately phonate, and was not able to move her right arm or leg against gravity. Her sensation appeared intact, and she had mild facial asymmetry with inability to raise the right corner of her mouth; her tongue had midline protrusion.

An emergent computed tomography (CT) scan of the head demonstrated mild brain atrophy and minimal low attenuation within the cerebral hemispheric white matter—most noticeably within the subcortical region of the left frontal lobe, consistent with small vessel ischemia. There was no evidence of acute intracranial hemorrhage, midline shift, or focal mass effect, and no convincing CT evidence for acute large vessel, cortical-based infarction.

The patient was determined to be an appropriate candidate for tPA, and was consented in the usual fashion. Within 15 minutes of administration of intravenous (IV) tPA, her symptoms improved, the aphasia resolved, and she was able to lift her right arm and leg against gravity and verbally communicate. Approximately 30 minutes following the resolution of her neurological symptoms, however, the patient was noted to have bleeding around a tooth socket, which was controlled with gauze and pressure. She subsequently began to complain of swelling on her right inferior lip without acute airway compromise. Over the next 10 to 15 minutes, she began to develop tongue swelling and feelings of dyspnea without wheezing.

The patient’s airway was reassessed and was classified as a Mallampati class IV. Anesthesia services were consulted for an emergent, awake intubation for airway protection. She was medicated with midazolam IV, as well as atomized lidocaine and lidocaine gargle for local anesthesia. The patient was successfully intubated awake using a flexible fiber optic technique. She was admitted to the medical intensive care unit for further monitoring, where she was treated with IV methylprednisolone, famotidine, and diphenhydramine. She was extubated the following day, had a relatively uncomplicated hospital course, and was discharged on hospital day 5 with improvement in her speech and right-sided weakness.

Discussion

The risk of angioedema associated with tPA administration has been previously described, with an estimated rate of 1.3 to 5.1%.^1-3 Studies have shown the risk of developing angioedema is significantly increased in the setting of concomitant use of an angiotensin converting enzyme inhibitor (ACE-I); CT studies have also shown evidence of frontal and insular ischemia, with an odds radio of 13.6 and 9.1, respectively.² Our patient was on lisinopril and had early signs of ischemia in the frontal lobe on initial CT scan, which likely increased her risk for angioedema.

How tPA Can Trigger Angioedema

The development of angioedema after administration of tPA has a well-described biochemical basis. Angioedema has been linked to the local vasodilatory effects of bradykinin, mast cell degranulation, and histamine release from activation of the complement pathway.⁴ Tissue plasminogen activator may trigger both of these pathways. It is a serine protease that cleaves plasminogen to plasmin; the plasmin in turn cleaves fibrin, resulting in the desired thrombolytic effects.⁵ Plasmin can cause mast cell degranulation through conversion of C3 to C3a and through activation of the complement pathway through conversion of C1 to C1a.⁶

Studies have shown tPA to have low antigenicity, and activation of this pathway is most likely secondary to direct proteolytic effects as opposed to antibody complexes.⁷ In a study by Bennett et al,⁶ tPA was shown to significantly increase C3a, C4a, and C5a  serum levels when given in the setting of myocardial infarction (MI). It has also been shown to activate and increase serum kallikrein, which cleaves high-molecular weight kininogen to bradykinin, a potent vasodilator.^8,9

Since bradykinin is broken down by several enzymes, including ACE, degradation is therefore delayed in patients on ACE-I.¹⁰ The alternate pathway for bradykinin degradation in the absence of ACE may also result in formation of des-Arg bradykinin, another similar active metabolite that mimics the effects of bradykinins.⁹ The formation of bradykinin through the proteolytic effects of tPA, in combination with the delayed breakdown in patient’s taking an ACE-I, likely plays a significant role in the development of angioedema.

In addition to the direct proteolytic effect of tPA resulting in angioedema, the underlying ischemic insult may also predispose patients to angioedema. As was the case with our patient, angioedema preferentially affects the ipsilateral side of the patient’s deficit.^2,11,12 Theories suggest this is due to the lack of autonomic compensatory responses in the setting of ischemic insult.² Interestingly, the development of angioedema in relation to the use of recombinant-tPA (eg, alteplase) in the setting of MI has not been as well described and may be related to the effect of central nervous system insult.³

Treatment

Although hemorrhagic complications of tPA therapy for cerebrovascular accident are well known, the risk for angioedema as a complication is less recognized. In most cases, angioedema is transient, and very few patients require aggressive support.^3,12 Treatments that have previously been described include antihistamines and steroids.^1,11,13 Epinephrine has been reported in one case study as an adjunct treatment of tPA-induced angioedema; however, it was given in combination with steroids and antihistimines.¹⁴ Therefore, caution should be taken regarding the use of epinephrine in this setting as there may be a theoretical precipitation of intracranial hypertension or hemorrhage.²

Given the likely significant role of the bradykinin-mediated pathway in tPA-induced angioedema, the true efficacy of these agents is unknown. Our patient had significant labial and lingual involvement, and given the concern for impending airway compromise, fiber optic intubation was performed. The decision to intubate and the technique employed must be carefully considered as a failed airway and need for a surgical airway is a concerning prospect in the setting of fibrinolytics. Successful cricothyroidotomy without significant complications has been described in the setting of streptokinase-induced angioedema when given for MI.¹⁵

Conclusion

The use of tPA for the treatment of ischemic stroke has been increasing over the last decade.^16,17 Given the high prevalence of ACE-I use in patients who are also at risk for ischemic stroke, physicians administering tPA must be aware of the risk of tPA-associated angioedema. Patients with a known history of angioedema or anaphylaxis to tPA should be counseled on these risks and should not be given this medication, but rather considered for potential endovascular or mechanical clot retrieval therapy if they meet inclusion criteria for its use.

The use of thrombolytic medications for the treatment of acute ischemic cerebral infarctions has dynamically altered stroke care. However, there are both major and minor side effects associated with its use—most notably major bleeding, which led to strict inclusion and exclusion criteria governing the administration of this medication class. One less recognized but potentially serious complication is angioedema secondary to tissue plasminogen activator (tPA). Our case emphasizes the importance of early recognition of this clinical syndrome as it relates to airway compromise and potential respiratory failure in patients who are treated with tPA.

Case

A 70-year-old woman with a history of diabetes and hypertension and a remote history of breast cancer, nonhemiplegic migraines, and hypothyroidism presented to the ED with complaints of aphasia and right-sided paralysis, with onset 2 hours prior. Regarding the patient’s medication history, she had been taking lisinopril for hypertension.

Upon assessment, the patient was awake and alert and her vital signs were normal and stable, but she was aphasic, unable to accurately phonate, and was not able to move her right arm or leg against gravity. Her sensation appeared intact, and she had mild facial asymmetry with inability to raise the right corner of her mouth; her tongue had midline protrusion.

An emergent computed tomography (CT) scan of the head demonstrated mild brain atrophy and minimal low attenuation within the cerebral hemispheric white matter—most noticeably within the subcortical region of the left frontal lobe, consistent with small vessel ischemia. There was no evidence of acute intracranial hemorrhage, midline shift, or focal mass effect, and no convincing CT evidence for acute large vessel, cortical-based infarction.

The patient was determined to be an appropriate candidate for tPA, and was consented in the usual fashion. Within 15 minutes of administration of intravenous (IV) tPA, her symptoms improved, the aphasia resolved, and she was able to lift her right arm and leg against gravity and verbally communicate. Approximately 30 minutes following the resolution of her neurological symptoms, however, the patient was noted to have bleeding around a tooth socket, which was controlled with gauze and pressure. She subsequently began to complain of swelling on her right inferior lip without acute airway compromise. Over the next 10 to 15 minutes, she began to develop tongue swelling and feelings of dyspnea without wheezing.

The patient’s airway was reassessed and was classified as a Mallampati class IV. Anesthesia services were consulted for an emergent, awake intubation for airway protection. She was medicated with midazolam IV, as well as atomized lidocaine and lidocaine gargle for local anesthesia. The patient was successfully intubated awake using a flexible fiber optic technique. She was admitted to the medical intensive care unit for further monitoring, where she was treated with IV methylprednisolone, famotidine, and diphenhydramine. She was extubated the following day, had a relatively uncomplicated hospital course, and was discharged on hospital day 5 with improvement in her speech and right-sided weakness.

Discussion

The risk of angioedema associated with tPA administration has been previously described, with an estimated rate of 1.3 to 5.1%.^1-3 Studies have shown the risk of developing angioedema is significantly increased in the setting of concomitant use of an angiotensin converting enzyme inhibitor (ACE-I); CT studies have also shown evidence of frontal and insular ischemia, with an odds radio of 13.6 and 9.1, respectively.² Our patient was on lisinopril and had early signs of ischemia in the frontal lobe on initial CT scan, which likely increased her risk for angioedema.

How tPA Can Trigger Angioedema

The development of angioedema after administration of tPA has a well-described biochemical basis. Angioedema has been linked to the local vasodilatory effects of bradykinin, mast cell degranulation, and histamine release from activation of the complement pathway.⁴ Tissue plasminogen activator may trigger both of these pathways. It is a serine protease that cleaves plasminogen to plasmin; the plasmin in turn cleaves fibrin, resulting in the desired thrombolytic effects.⁵ Plasmin can cause mast cell degranulation through conversion of C3 to C3a and through activation of the complement pathway through conversion of C1 to C1a.⁶

Studies have shown tPA to have low antigenicity, and activation of this pathway is most likely secondary to direct proteolytic effects as opposed to antibody complexes.⁷ In a study by Bennett et al,⁶ tPA was shown to significantly increase C3a, C4a, and C5a  serum levels when given in the setting of myocardial infarction (MI). It has also been shown to activate and increase serum kallikrein, which cleaves high-molecular weight kininogen to bradykinin, a potent vasodilator.^8,9

Since bradykinin is broken down by several enzymes, including ACE, degradation is therefore delayed in patients on ACE-I.¹⁰ The alternate pathway for bradykinin degradation in the absence of ACE may also result in formation of des-Arg bradykinin, another similar active metabolite that mimics the effects of bradykinins.⁹ The formation of bradykinin through the proteolytic effects of tPA, in combination with the delayed breakdown in patient’s taking an ACE-I, likely plays a significant role in the development of angioedema.

In addition to the direct proteolytic effect of tPA resulting in angioedema, the underlying ischemic insult may also predispose patients to angioedema. As was the case with our patient, angioedema preferentially affects the ipsilateral side of the patient’s deficit.^2,11,12 Theories suggest this is due to the lack of autonomic compensatory responses in the setting of ischemic insult.² Interestingly, the development of angioedema in relation to the use of recombinant-tPA (eg, alteplase) in the setting of MI has not been as well described and may be related to the effect of central nervous system insult.³

Treatment

Although hemorrhagic complications of tPA therapy for cerebrovascular accident are well known, the risk for angioedema as a complication is less recognized. In most cases, angioedema is transient, and very few patients require aggressive support.^3,12 Treatments that have previously been described include antihistamines and steroids.^1,11,13 Epinephrine has been reported in one case study as an adjunct treatment of tPA-induced angioedema; however, it was given in combination with steroids and antihistimines.¹⁴ Therefore, caution should be taken regarding the use of epinephrine in this setting as there may be a theoretical precipitation of intracranial hypertension or hemorrhage.²

Given the likely significant role of the bradykinin-mediated pathway in tPA-induced angioedema, the true efficacy of these agents is unknown. Our patient had significant labial and lingual involvement, and given the concern for impending airway compromise, fiber optic intubation was performed. The decision to intubate and the technique employed must be carefully considered as a failed airway and need for a surgical airway is a concerning prospect in the setting of fibrinolytics. Successful cricothyroidotomy without significant complications has been described in the setting of streptokinase-induced angioedema when given for MI.¹⁵

Conclusion

The use of tPA for the treatment of ischemic stroke has been increasing over the last decade.^16,17 Given the high prevalence of ACE-I use in patients who are also at risk for ischemic stroke, physicians administering tPA must be aware of the risk of tPA-associated angioedema. Patients with a known history of angioedema or anaphylaxis to tPA should be counseled on these risks and should not be given this medication, but rather considered for potential endovascular or mechanical clot retrieval therapy if they meet inclusion criteria for its use.

The use of thrombolytic medications for the treatment of acute ischemic cerebral infarctions has dynamically altered stroke care. However, there are both major and minor side effects associated with its use—most notably major bleeding, which led to strict inclusion and exclusion criteria governing the administration of this medication class. One less recognized but potentially serious complication is angioedema secondary to tissue plasminogen activator (tPA). Our case emphasizes the importance of early recognition of this clinical syndrome as it relates to airway compromise and potential respiratory failure in patients who are treated with tPA.

Case

A 70-year-old woman with a history of diabetes and hypertension and a remote history of breast cancer, nonhemiplegic migraines, and hypothyroidism presented to the ED with complaints of aphasia and right-sided paralysis, with onset 2 hours prior. Regarding the patient’s medication history, she had been taking lisinopril for hypertension.

Upon assessment, the patient was awake and alert and her vital signs were normal and stable, but she was aphasic, unable to accurately phonate, and was not able to move her right arm or leg against gravity. Her sensation appeared intact, and she had mild facial asymmetry with inability to raise the right corner of her mouth; her tongue had midline protrusion.

An emergent computed tomography (CT) scan of the head demonstrated mild brain atrophy and minimal low attenuation within the cerebral hemispheric white matter—most noticeably within the subcortical region of the left frontal lobe, consistent with small vessel ischemia. There was no evidence of acute intracranial hemorrhage, midline shift, or focal mass effect, and no convincing CT evidence for acute large vessel, cortical-based infarction.

The patient was determined to be an appropriate candidate for tPA, and was consented in the usual fashion. Within 15 minutes of administration of intravenous (IV) tPA, her symptoms improved, the aphasia resolved, and she was able to lift her right arm and leg against gravity and verbally communicate. Approximately 30 minutes following the resolution of her neurological symptoms, however, the patient was noted to have bleeding around a tooth socket, which was controlled with gauze and pressure. She subsequently began to complain of swelling on her right inferior lip without acute airway compromise. Over the next 10 to 15 minutes, she began to develop tongue swelling and feelings of dyspnea without wheezing.

The patient’s airway was reassessed and was classified as a Mallampati class IV. Anesthesia services were consulted for an emergent, awake intubation for airway protection. She was medicated with midazolam IV, as well as atomized lidocaine and lidocaine gargle for local anesthesia. The patient was successfully intubated awake using a flexible fiber optic technique. She was admitted to the medical intensive care unit for further monitoring, where she was treated with IV methylprednisolone, famotidine, and diphenhydramine. She was extubated the following day, had a relatively uncomplicated hospital course, and was discharged on hospital day 5 with improvement in her speech and right-sided weakness.

Discussion

The risk of angioedema associated with tPA administration has been previously described, with an estimated rate of 1.3 to 5.1%.^1-3 Studies have shown the risk of developing angioedema is significantly increased in the setting of concomitant use of an angiotensin converting enzyme inhibitor (ACE-I); CT studies have also shown evidence of frontal and insular ischemia, with an odds radio of 13.6 and 9.1, respectively.² Our patient was on lisinopril and had early signs of ischemia in the frontal lobe on initial CT scan, which likely increased her risk for angioedema.

How tPA Can Trigger Angioedema

The development of angioedema after administration of tPA has a well-described biochemical basis. Angioedema has been linked to the local vasodilatory effects of bradykinin, mast cell degranulation, and histamine release from activation of the complement pathway.⁴ Tissue plasminogen activator may trigger both of these pathways. It is a serine protease that cleaves plasminogen to plasmin; the plasmin in turn cleaves fibrin, resulting in the desired thrombolytic effects.⁵ Plasmin can cause mast cell degranulation through conversion of C3 to C3a and through activation of the complement pathway through conversion of C1 to C1a.⁶

Studies have shown tPA to have low antigenicity, and activation of this pathway is most likely secondary to direct proteolytic effects as opposed to antibody complexes.⁷ In a study by Bennett et al,⁶ tPA was shown to significantly increase C3a, C4a, and C5a  serum levels when given in the setting of myocardial infarction (MI). It has also been shown to activate and increase serum kallikrein, which cleaves high-molecular weight kininogen to bradykinin, a potent vasodilator.^8,9

Since bradykinin is broken down by several enzymes, including ACE, degradation is therefore delayed in patients on ACE-I.¹⁰ The alternate pathway for bradykinin degradation in the absence of ACE may also result in formation of des-Arg bradykinin, another similar active metabolite that mimics the effects of bradykinins.⁹ The formation of bradykinin through the proteolytic effects of tPA, in combination with the delayed breakdown in patient’s taking an ACE-I, likely plays a significant role in the development of angioedema.

In addition to the direct proteolytic effect of tPA resulting in angioedema, the underlying ischemic insult may also predispose patients to angioedema. As was the case with our patient, angioedema preferentially affects the ipsilateral side of the patient’s deficit.^2,11,12 Theories suggest this is due to the lack of autonomic compensatory responses in the setting of ischemic insult.² Interestingly, the development of angioedema in relation to the use of recombinant-tPA (eg, alteplase) in the setting of MI has not been as well described and may be related to the effect of central nervous system insult.³

Treatment

Although hemorrhagic complications of tPA therapy for cerebrovascular accident are well known, the risk for angioedema as a complication is less recognized. In most cases, angioedema is transient, and very few patients require aggressive support.^3,12 Treatments that have previously been described include antihistamines and steroids.^1,11,13 Epinephrine has been reported in one case study as an adjunct treatment of tPA-induced angioedema; however, it was given in combination with steroids and antihistimines.¹⁴ Therefore, caution should be taken regarding the use of epinephrine in this setting as there may be a theoretical precipitation of intracranial hypertension or hemorrhage.²

Given the likely significant role of the bradykinin-mediated pathway in tPA-induced angioedema, the true efficacy of these agents is unknown. Our patient had significant labial and lingual involvement, and given the concern for impending airway compromise, fiber optic intubation was performed. The decision to intubate and the technique employed must be carefully considered as a failed airway and need for a surgical airway is a concerning prospect in the setting of fibrinolytics. Successful cricothyroidotomy without significant complications has been described in the setting of streptokinase-induced angioedema when given for MI.¹⁵

Conclusion

The use of tPA for the treatment of ischemic stroke has been increasing over the last decade.^16,17 Given the high prevalence of ACE-I use in patients who are also at risk for ischemic stroke, physicians administering tPA must be aware of the risk of tPA-associated angioedema. Patients with a known history of angioedema or anaphylaxis to tPA should be counseled on these risks and should not be given this medication, but rather considered for potential endovascular or mechanical clot retrieval therapy if they meet inclusion criteria for its use.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is characterized by a balanced translocation between chromosomes 15 and 17 [t(15;17)], which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes.^1,2 Historically, APL was a fatal disease because of the high relapse rates with cytotoxic chemotherapy alone and a significant bleeding risk secondary to disseminated intravascular coagulation (DIC).

Click on the PDF icon at the top of this introduction to read the full article.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is characterized by a balanced translocation between chromosomes 15 and 17 [t(15;17)], which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes.^1,2 Historically, APL was a fatal disease because of the high relapse rates with cytotoxic chemotherapy alone and a significant bleeding risk secondary to disseminated intravascular coagulation (DIC).

Click on the PDF icon at the top of this introduction to read the full article.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) that is characterized by a balanced translocation between chromosomes 15 and 17 [t(15;17)], which results in the fusion of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes.^1,2 Historically, APL was a fatal disease because of the high relapse rates with cytotoxic chemotherapy alone and a significant bleeding risk secondary to disseminated intravascular coagulation (DIC).

Click on the PDF icon at the top of this introduction to read the full article.