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Volume 29 / Issue 1 / January-June 2015

ISSN 0972-6691

Indian Journal of Allergy, Asthma & Immunology

Official Publication of Indian College of Allergy, Asthma and Applied Immunology (ICAAI)

India

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© 2015 Indian Journal of Allergy, Asthma and Immunology | Published by Wolters Kluwer ‑ Medknow46

Sporadic nonfamily case of hereditary angioedema type III presenting as recurrent abdominal pain with intestinal

obstruction in women with primary infertility

Arun Agarwal, Mamta Agarwal

Department of Internal Medicine and Radiodiagnosis, Malviya Nagar Clinic and Sonography Centre, Jaipur, Rajasthan, India

Address for correspondence: Dr. Arun Agarwal, A‑235, Shivanand Marg, Malviya Nagar, Jaipur ‑ 302 017, Rajasthan, India. E‑mail: mpicdrarun@gmail.com

ABSTRACT

Hereditary angioedema (HAE) is a debilitating disorder that can substantially impair quality of life. Three types of HAE are described in literature. Women are particularly prone to attacks due to multiple estrogen‑related triggers. Abdominal involvement in angioedema is often a challenge to diagnose. Recurrent or acute onset abdominal pain can be the only presenting symptom, and misdiagnosis may lead to unnecessary surgical intervention. Clinicians need to be familiar with the types and presentations of the various types of angioedema. The knowledge about new, effective, and safe therapies, along with an increased awareness of HAE and its related concerns should help clinicians in providing optimal treatment to their patients and avoid unnecessary surgical interventions. We report a sporadic nonfamily case of HAE type III presenting as recurrent abdominal pain with intestinal obstruction in women with primary infertility.

Key words: Acquired angioedema, Angiotensin converting enzyme induced angioedema, C1 esterase inhibitor‑functional and antigenic, gastrointestinal, hereditary angioedema, idiopathic angioedema

INTRODUCTION

Since the first comprehensive clinical description of HAE in 1888, the knowledge of the disease has been ever expanding. Broadly angioedema are diseases characterized by transient and recurrent attacks of subcutaneous or mucosal edema, referred to as “attacks.” The severity and frequency is extremely variable among patients and even in the same patient at different times in their life. Thus it is a clinical syndrome with a mediator and

case report

multiple causes. Some attacks are life threatening. Intestinal angioedema is less commonly encountered by emergency physicians (EPs) than angioedema of the lips and tongue and therefore may be unrecognized. Prompt detection and treatment of this rare disease can significantly improve patient outcome by minimizing morbidity from misdiagnosis or unnecessary operative interventions.

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DOI: 10.4103/0972-6691.162986

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How to cite this article: Agarwal A, Agarwal M. Sporadic nonfamily case of hereditary angioedema type III presenting as recurrent abdominal pain with intestinal obstruction in women with primary infertility. Indian J Allergy Asthma Immunol 2015;29:46-50.

Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III

47Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 1 47

CASE REPORT

Ms. RA, 38 years, a known case of primary infertility was first seen on March 31, 2015, for cutaneous angioedema involving face and torso. She had no urticaria and had similar symptoms off and on for 4 years (usually self‑limiting). There was no history of taking aspirin, ACE inhibitors, angiotensin receptor blockers (ARB’s), or history of malignancy, autoimmune disease, or drug causing change in estrogen levels. She had no family history of similar illness. She was given H1 blockers (ebastine), H2 blockers (ranitidine), and steroids (deflazacort). She developed abdominal pain with distention, gaseousness, vomiting, facial edema, and throat discomfort on April 12, 2015, and was admitted to another nursing home where she was diagnosed to have sub‑acute intestinal obstruction and managed conservatively with antibiotics, fluids, and supportive treatment. She revisited clinic on April 14, 2015, and had mild facial puffiness and lip swelling. She was suspected to have hereditary angioedema (HAE) and was further evaluated. Her investigations are tabulated in Table 1. She developed similar abdominal symptoms on April 29, 2015, and a contrast‑enhanced computed tomography (CECT) abdomen was done which showed multiple segments of thickening of walls of ileum of varying length (longest being approximately 9 cm) with resultant luminal narrowing [Figure 1]. She recovered spontaneously within 3–5 days. On further questioning she revealed that she had similar mild abdominal pains off and on since 2003, but it was attributed to mild pelvic endometriosis diagnosed during her work up of primary infertility and in vitro fertilization treatment. However, these two attacks were severe. With normal complement and C1‑INH (both functional and quantitative) she was diagnosed to have HAE type III (sporadic case) and started on prophylactic Danazol treatment. In the meantime other opinions were sought and she was evaluated for celiac disease and inflammatory bowel disease and was given options of capsule video endoscopy and a therapeutic trial for Crohn’s disease. Barium meal follow through done on May 11, 2015, and a repeat CECT abdomen done on May 26, 2015, were normal [Table 2, Figures 2 and 3]. She is at present on Danazol and had no further episode of angioedema till end of July 2015.

DISCUSSION

HAE is an autosomal dominant rare, debilitating disease that impairs quality of life. About 10–20% of people worldwide will develop an episode of angioedema or urticaria at some point in their lifetime, women being more prone than men.[1] The prevalence of HAE is around 1/100,000, and involves almost all races.[2] The term “angioedema” describes a circumscribed edema of the skin, gastrointestinal (GI) tract

Figure 1: Contrast‑enhanced computed tomography abdomen (coronal view) done on April 30, 2015, showing multiple

segmental ileal luminal narrowing (arrows)

Figure 2: Barium meal and follow through done on May 11, 2015 showing complete resolution of ileal narrowing

Figure 3: Contrast‑enhanced computed tomography abdomen done on May 26, 2015 showing complete resolution of multiple

segmental ileal narrowing [compare with Figure 1]

Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III

Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 148

or respiratory tract. The majority of cases are HAE, acquired angioedema (AAE) or idiopathic angioedema (IAE). The salient features of various types of AE are presented in

Table 3. EP needs to differentiate between histamine and bradykinin mediated angioedema. In a bradykinin mediated angioedema there is no itching or urticaria and treatment with corticosteroids and antihistamines is not effective.

In HAE, there is a mutation in the gene that encodes the C1‑INH of the complement factor (INHC1), inducing a reduction in its synthesis (type I HAE) or the formation of a dysfunctional protein (type II HAE). In 2000, a new subtype of HAE was described, which is clinically indistinguishable from the others, predominantly in women, in which the INHC1 is normal.[3] This new disorder was called HAE type III, estrogen‑dependent HAE or HAE with normal C1 activity (type III HAE). It is very rare and found predominantly in women and may be due to known mutations in the factor XII gene (F12) or to unknown genetic mutations.[4] Studies have reported first episode or recurrences associated with estrogen containing oral contraceptives, estrogen replacement therapy or pregnancy, thereby suggesting a direct correlation with estrogen levels. Our patient had no such history but rather had primary infertility.

In angioedema localized temporary swelling occurs, which can involve all layers of the skin or walls of hollow viscera, such as pharynx, respiratory system, or the GI tract. Symptoms may include peripheral nonpitting edema (skin), swelling of lips, tongue (opharynx) and genitalia, difficulty in breathing (larynx), nausea, vomiting, diarrhea, features of intestinal obstruction, and abdominal pain of varying degree (GI tract). Abdominal pain may manifest as severe acute onset abdominal pain, or as chronic recurrent abdominal pain of moderate severity.[5] In one study, misdiagnosis of abdominal symptoms had even led to unnecessary appendectomy, laparotomy, or both, in 35% of patients.[6] However, surgical exploration of abdominal symptoms should be avoided in the absence of signs of acute abdomen (i.e., absence of fever, leukocytosis, or peritoneal signs; presence of bowel sounds).[7] Our patient had severe attacks with symptoms consistent with intestinal obstruction

Table 2: Imaging of the patientDate Test Imaging resultsApril 30, 2015 CECT abdomen Multiple segments of thickening of walls of

ileum of varying length, longest segment of approximately 9 cm with resultant luminal narrowing

May 11, 2015 Barium meal follow through

Normal. No definite stricture or dilated gut loop seen

May 26, 2015 CECT abdomen No abnormality seen. Multiple segmental areas of narrowing seen involving the ileum in CECT dated April 30, 2015 are no longer seen

CECT ‑ Contrast enhanced computed tomography

Table 3: Mediator, distinguishing features and complement profile in angioedema syndromesHAE type I HAE type II HAE type III AAE IAE ACE‑I NSAID Allergic AE with urticarial

vasculitisMediator Bradykinin Bradykinin Bradykinin Bradykinin Unknown

NonhistaminergicBradykinin Leukotriens Histamine Histamine/

leukotriensFamily history Yes Yes Yes No No No No No Yes/noUrticaria No No No No Usually No Usually Usually UsuallyLocation Anywhere Anywhere Anywhere Anywhere Especially lips

and faceEspecially lips, tongue and intestine

Especially face

Anywhere Usually skin

Age at onset in years 6‑20 6‑20 6‑20 >40 Any Any Any Any >15C4 Low Low Normal Low Normal Normal Normal Normal LowC1 INH antigenic Low Normal Normal Low (type I)

Low/normal (type II)Normal Normal Normal Normal Normal

C1 INH functional Low Low Normal Low Normal Normal Normal Normal NormalC1q Normal Normal Normal Low (type I)

Low/normal (type II)Normal Normal Normal Normal Low

C3 Low Low Normal Low Normal Normal Normal Normal LowHAE ‑ Hereditary angioedema, AAE ‑ Acquired angioedema, IAE ‑ Idiopathic angioedema, ACE‑I ‑ Angiotensin converting enzyme inhibitor, NSAID ‑ Nonsteroidal anti‑inflammatory drug, C1 INH ‑ C1 esterase inhibitor

Table 1: Hematological and other investigationsDate Investigation Result Unit Reference rangeMarch 31, 2015 C3 235.67 mg/dL 75‑135

C4 37.49 mg/dL 10‑40TLC 5.5 ×103/µL 3.5‑11.5Hb 10.7 g/dL 13‑16Platelet count 246 ×103/µL 150‑410TEC 105 Cmm 20‑500VEC 0 % TEC NilUrine Normal

April 14, 2015 C1 esterase inhibitorProtein (quantitative)

247 mg/L 195‑345

C1 INHFunctional

84.8 % 68

April 30, 2015 CRP 26.4 mg/L <5ESR 18 mm 1 h 0‑20tTG IgA antibodies 1.6 U/mL <12P ANCA and C ANCA Negative

May 05, 2015 Stool test routine NormalESR 22 mm 1 h 0‑20CRP 5.1 mg/L <5

May 06, 2015 ASCA IgA saccharomycesCerevisiae

11.2 U/mL <10

ASCA IgG saccharomycesCerevisiae

67.8 U/mL <10

CRP 3.1 mg/L <5TLC ‑ Total leucocyte count, TEC ‑ Total eosinophil count, VEC ‑ Vacuolated eosinophil count, CRP ‑ C‑reactive protein, ESR ‑ Erythrocyte sedimentation rate, tTG ‑ Tissue transglutaminase antibody, ASCA ‑ Anti‑saccharomyces cerevisiae antibodies, ANCA ‑ Anti‑neutrophil cytoplasmic antibody, C1 INH ‑ C1 esterase inhibitor

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49Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 1 49

on two occasions and was even referred to GI surgeon after CECT showed ileal luminal narrowing at multiple levels. However, it resolved within 3–5 days and subsequent barium meal and follow through examination and CECT scan abdomen did not show any features of intestinal obstruction. Thus, alternate diagnoses for recurrent abdominal symptoms should always be considered to avoid unnecessary surgical procedures as patients presenting only with abdominal signs and symptoms have been described in literature with no cutaneous, oropharyngeal or respiratory involvement.[8,9]

The differential diagnosis includes AAE and IAE. In AAE, there is no familial inheritance, and it can occur at a later age than HAE. The condition develops as a result of increased consumption of C1‑INH or impairment of C1‑INH function due to autoantibody formation. AAE is divided into four groups: (1) AAE‑I ‑ resulting from paraneoplastic syndrome or development of auto antibodies which enhances cleavage of C1‑INH, leading to C1‑INH dysfunction; (2) AAE‑II ‑ resulting from autoimmune disease; (3) AAE ‑ associated with sex hormones, especially during pregnancy; and (4) drug‑induced AAE ‑ particular associated with ACE INHs or ARB’s.[10] Our patient had no such feature to suggest AAE. IAE is usually associated with urticaria. Thyroid dysfunction is common with this form and should be ruled out. The mechanism of this disease is unknown.[10] Our patient did not had any urticaria or thyroid dysfunction.

The inheritance pattern of HAE type III has a genetic polymorphism that contributes to phenotypic diversity of HAE type III[11] A family history of angioedema strongly supports the diagnosis, but it is not required, since approximately one‑quarter of patients have de novo mutations. There are reports of nonfamily cases, sporadic, that could present new genetic mutations, different to those already described so far and still unknown.[12] Although criteria for diagnosis of angioedema caused by C1‑INH deficiency have been described, no diagnostic criteria have been defined so far for HAE type III. HAE type III, to date manifest only in women, and its symptoms closely resemble those associated with functional C1‑INH deficiency but occur in the presence of normal C1‑INH concentrations; the genetic defect responsible is currently unknown.[13] Genetic tests that could classify her with a genetic alteration were not performed due to the nonavailability of such tests in our facilities. Thus, with normal C1‑INH (antigenic and functional) levels, history of recurrent angioedema, spontaneous remission over 3–5 days, recurrent abdominal symptoms with imaging findings, no history/cause to suggest other causes of angioedema, she was diagnosed as a sporadic nonfamily case of HAE type III. IAE looked unlikely looking to absence of urticaria and response to long‑term prophylaxis with Danazol. She had no further attack till July 31, 2015. It is also important to recognize that all attacks localized

over the shoulder (face, neck, throat, and respiratory tract) and all abdominal attacks with pain rated >5 on the visual analogue scale are considered severe.

Treatment options of HAE involve prophylaxis ‑ both short‑term and long‑term; and acute treatment.• Short‑term prophylaxis: Three options of attenuated

androgens, tranexamic acid or C1‑INH concentrate are available. There is no specific problem for the use of these drugs for the short‑term in female patients. In case of short‑term prophylaxis with attenuated androgens, no virilization has been observed[14,15]

• Long‑term prophylaxis: Attenuated androgens (Danazol), anti‑fibrinolytics (tranexamic acid) and plasma derived C1‑INH (pdC1‑INH) are used. Attenuated androgens are highly effective but are accompanied by side effects. The result of PREHAET study (presented by Bork) reported a weight gain for 30% of women, virilisation for 6%, menstrual irregularities for 30%, acne for 7% along with alopecia, hirsutism, and mammary hypotrophy.[16] However, they are dose dependant and can be decreased by titrating the dose to lowest effective level. Anti‑fibrinolytics have good tolerance, moderate efficacy and adverse effects as nausea, diarrhea and a theoretical risk of thromboembolism. pdC1‑INH was approved by Food and Drug Administration in 2008 for long‑term prophylaxis. It is not available in India.

Acute treatmentTreatment guidelines for HAE recommend the use of the bradykinin receptor blocker (icatibant) or the kallikrein INH (ecallantide) for the treatment of acute attacks.[17] In the United States, ecallantide and the pdC1‑INH were approved in 2009, and the bradykinin receptor blocker icatibant was approved in 2011 for the treatment of acute attacks of HAE. Since all three are not available in India, using fresh frozen plasma (FFP) in acute attack is a reasonable choice and an infusion of 2‑4 U of FFP is useful in replacing INH levels.[18] Rarely the swelling can become worse due to complement factors present in FFP. The only option for acute settings in our case could have been use of FFP. Our patient is in long‑term prophylaxis with Danazol.

The major issue still is the difficulty that many patients have in reaching correct diagnosis and treatment. Deaths and unwanted surgeries caused by HAE and similar angioedematous disorders still occur. The EPs, ignoring the existence of HAE, still label these patients as allergic. We hope that this case report will help bring more HAE, AAE, and IAE patients to the correct diagnosis.

On literature search, we did not find any case report of a sporadic nonfamily case of HAE type III presenting as abdominal pain with intestinal obstruction in women with primary infertility.

Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III

Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 150

CONCLUSION AND TAKE HOME MESSAGE

• HAEwithnormalC1‑INH(HAEtypeIII)isclinicallycharacterized by recurrent angioedema affecting the skin, GI tract, and larynx

• HAEcanrarelypresentasanonfamily,sporadiccase• HAEshouldberecognizedinitsvariousformsand

especially as a cause of recurrent unexplained abdominal pain so that unnecessary invasive procedures and hospitalizations can be avoided and long‑term prophylaxis therapy can be administered. Prompt detection and treatment of this rare disease can significantly improve patient outcome by minimizing morbidity

• EPsshoulddifferentiatebetweenhistamineandBradykinin mediated angioedema and recognizes “attacks” that are considered severe.

Financial support and sponsorshipNil.

Conflicts of interestThere are no conflicts of interest.

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