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Year : 2020  |  Volume : 34  |  Issue : 1  |  Page : 49-52

Spectrum of diagnosis of hereditary angioedema: Seven case reports

1 National Allergy Centre, BLK Super Specialty Hospital, Delhi, India
2 National Allergy Centre, Delhi, India

Date of Submission12-Dec-2019
Date of Acceptance20-Apr-2020
Date of Web Publication6-Jul-2020

Correspondence Address:
Dr. P C Kathuria
National Allergy Centre, 1/3, East Patel Nagar, New Delhi - 110 008
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijaai.ijaai_33_19

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Hereditary angioedema (HAE) is a potentially life-threatening disorder, due to a mutation in complement one-inhibitor (C1-INH) gene, which blocks the activity of various components of complement – fibrinolytic and bradykinin control system. Our seven cases of HAE give different clinical presentations of TYPE I/II/III HAE as facial, abdominal, laryngeal, and genital involvement along with comorbidities (5 cases) such as hypothyroidism, rhinosinusitis, and hypothalamic–pituitary–adrenal suppression, and four cases have had history of recurrent abdominal attacks. Treatment with Pdc-INH concentrate and self-administrated Icatibant provides consistent and reliable efficacy in those who have had multiple successive HAE attacks, with the involvement of all body parts. However, if pdc-INH concentrate is not available, then fresh frozen plasma and androgens (Danazol) can be used in emergency. Our cases demonstrate the importance of diligent clinical and family history with special tests: C4, C1-INH quantitative, and C1-INH functional.

Keywords: C1-inhibitor, C3, C4, fresh frozen plasma, hereditary angioedema, hypothalamus–pituitary–adrenal axis suppression

How to cite this article:
Kathuria P C, Rai M, Kathuria N. Spectrum of diagnosis of hereditary angioedema: Seven case reports. Indian J Allergy Asthma Immunol 2020;34:49-52

How to cite this URL:
Kathuria P C, Rai M, Kathuria N. Spectrum of diagnosis of hereditary angioedema: Seven case reports. Indian J Allergy Asthma Immunol [serial online] 2020 [cited 2023 Feb 8];34:49-52. Available from: https://www.ijaai.in/text.asp?2020/34/1/49/289066

  Introduction Top

Hereditary angioedema (HAE) is an autosomal dominant disease due to deficiency and dysfunctional complement one (C1) esterase inhibitor (INH) antigenic protein. The incidence and prevalence in India have not been established as there is no registry for HAE in India. There are approximately 30,000–50,000 affected patients in India. Most of the cases are managed by dermatologists, gastroenterologists, and clinical allergists.[1] C1 INH is the first step in the complement cascade, and it prevents C1 from cleaving C4 that is why, C4 is almost always low in this disease and is the first screening test. Eighty-percent of Type I HAE has low C1 INH enzyme and 20% of Type II has normal or even high C1 INH enzyme but dysfunctional. Laboratory investigation (C4/C1 INH protein and C1 INH-functional) are done by selected centers in India, but C1 q is outsourced from India.[2] Long-term prophylaxis is considered, only in selected cases if the disease is progressive (moderate to severe) attack of laryngeal edema or impairment in daily normal activities. Androgens (Danazol/Stanazolol) are started in higher dose (400–600 mg day) and tapered to minimum effective doses (50–200 mg, twice a week), with regular monitoring of LFT and lipid profile. If there is relative/absolute contraindication to the use of androgens, then only therapy is C1-INH concentrate as long-term prophylaxis (not available in India). Even though the patients are on long-term prophylaxis, they may get acute attacks of life-threatening laryngeal edema, where either pd. C1-INH concentrate or anti-kallikrain INH (Ecallantide) and bradykinin beta-2 receptor antagonist (Icatibant) are given on demand therapy (not available in India); we still manage our patient with fresh frozen plasma (FFP) at the time of acute attacks though it is not an ideal therapeutic agent. In case of any surgical intervention (elective/emergency surgery such as gallbladder and head and neck surgery), the drug of choice is pd C1 INH concentrate (not available in India). We give solvent detergent-reacted plasma or FFP 1–6 h before procedure at the rate of 10 ml/kg (400–800 ml in adults). In mild-to-moderate attack, only demand therapy is given; however, if the attack is moderate-to-severe and life-threatening, then long-term prophylaxis is to be given. With the advent of serological tests and modern drugs, patients of HAE can have a normal healthy life, and if early diagnosis and early treatment is given, the duration of each attack is reduced to 1–3 h from duration of 3–5 days.[3],[4] We report seven case scenarios from our National Allergy Centre as discussed in this article, five cases of Type I HAE (low C4 and low C1 INH quantitative), one case of Type II HAE (low C4 and low C1 INH functional), and one case of Type III HAE (low C4 and normal C1 INH-quantitative and functional), but the patient was on oral contraceptives.

  Case Report Top

Case 1: Type III hereditary angioedema with normal complement one-inhibitor (abdominal attacks and hypothyroidism)

A 26-year-old female presented with hypothyroidism and history of swelling all over the body not associated with itching but associated with pain abdomen for 7 years. She was advised exploratory laprotomy 3 years ago due to recurrent severe pain abdomen but was diagnosed with HAE because of low C4 level and was given FFP following which the symptoms subsided and was started on tablet Danazol 100 mg Thrice a day (TDS). She also gave a history of multiple abortions. There were no history of laryngeal edema and no family history. Her C1 INH and C3 were normal but C4 was low, while thyroid stimulating hormone was markedly raised [Table 1]. She had history of regular oral contraceptives intake and her blood estrogen level was raised
Table 1: Blood Investigations report

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Case 2: Type I hereditary angioedema (abdominal attacks with hypothalamic–pituitary–adrenal suppression)

A 42-year-old male presented with a history of generalized urticaria with itching on and off for 30 years. He also gave a history of severe pain abdomen which only subsided on intravenous analgesics for which diagnostic endoscopy was done which revealed esoinophilic enteropathy. There is no history of any swelling during these episodes. He also had complaints of multiple joint pains. He had low serum cortisol with low quantitative C1 INH and normal C3, C4 [Table 1], which could be due to hypothalamic-pituitary-adrenal suppression. There is no family history of similar complaints.

Case 3: Type II hereditary angioedema (cutaneous symptoms with chronic allergic rhinosinusitis)

An 18-year-old male gave a history of isolated left lower limb swelling 7 years back which subsided on its own in 2–3 days and generalized swelling on and off for 1 year. No history of laryngeal edema or pain abdomen was noted. There was also history of recurrent rhinitis for 15 years and X-ray paranasal sinuses was suggestive of B/L maxillary polyp with acute on chronic maxillary sinusitis. His functional C1-INH was low, while C1-INH quantitative and C4 were normal. Total IgE was also raised with borderline Absolute Eosinophil Count (AEC) [Table 1]. There is no family history of similar complaints.

Case 4: Type I hereditary angioedema (cutaneous and laryngeal attack)

A 42-year-old female presented with history of multiple episodes of facial edema and swelling in the bilateral extremities for 30 years. A history of associated laryngeal edema during 3–4 such episodes was noted. The swelling was not associated with itching and subsided on its own in 3–4 days. There was history of exacerbation both in number and severity during her pregnancy and was associated with laryngeal edema. No history of pain abdomen and no family history were noted. Her C1-INH quantitative, C1 INH functional, and C4 was low [Table 1]. Total IgE was normal.

Case 5: Type I hereditary angioedema (cutaneous and abdominal attacks)

A 27-year-old male presented with history of generalized swelling associated with pain abdomen and exertional shortness of breath on and off for 10 years of age. There was no itching and the symptoms subsided without medication in 2–3 days. There was no history of laryngeal edema. He had a strong family history with his mother, brother, and sister having similar complaints. He had low C4 and normal C1-INH.

Case 6: Type I hereditary angioedema (cutaneous and genitalia involvement with hypothyroidism)

A 15-year-old female patient recently diagnosed with hypothyroidism presented with history of facial and laryngeal edema, 3–4 episodes for 1 year. She was given intravenous corticosteroids on all occasions following which the edema subsided in 24–36 h. She also gave a history of bilateral hands and feet swelling with genitalia involvement, which subsided on its own without treatment. The swelling is not associated with itching or pain abdomen. Her mother had similar complaints and was a diagnosed case of HAE. Her C4, C1 INH quantitative, and C1 INH functional were low [Table 1]. Total IgE and AEC were normal.

Case 7: Type I hereditary angioedema (abdominal attacks and hypothyroidism)

A 21-year-old male presented with history of facial swelling not associated with itching on and off for 12 years of age He also gave a history of severe pain abdomen; ultrasonography abdomen revealed mild-to-moderate ascitis on multiple occasions. He was even hospitalized twice for pain abdomen. There is no history of laryngeal edema. He is a known case of polycythemia, hypothyroidism, and was recently diagnosed with hypertension 1 year ago. He had a strong family history with his grandfather, father, step brother, and step sister having similar complaints of facial swelling and pain abdomen. His C1 INH quantitative, C1 INH functional, and C4 were low [Table 1].

  Discussion Top

There are three types of HAEType I seen in 85% of cases, and they have low C1 INH quantitative levels, which is responsible for angioedema. Type II was seen in 15% of cases where C1 INH concentration is normal but functional protein has got abnormal action. Type III resembles HAE but occurs in females only. Additional types of angioedema include acquired C1 INH deficiency, angiotensin converting enzyme INH-associated angioedema, idiopathic angioedema, allergic angioedema, nonsteroidal anti-inflammatory drug-associated angioedema, and angioedema associated with urticarial vasculitis. Most of these have normal C4 levels; however, like HAE Type 1 or 2, acquired C1 INH deficiency and urticarial vasculitis can have reduced C4 levels. Forty percent of the patients of HAE get symptoms before 5 years of age while 75% before 15 years of age. However, Type III occurs after 30 years of age. Six of our patients have had symptoms for several years before being diagnosed, while one of them has had recurrent episodes only for 1 year. 25%–30% of HAE patients have abdominal edema and laryngeal edema.[5] Among our seven cases, four cases had abdominal attacks while one patient had multiple episodes of laryngeal edema. In one study, it was found that almost half of the attacks involved the abdomen and almost all patients with Type I or Type II disease experience at least one such abdominal attack whereas almost one-third of the patients with undiagnosed HAE undergo unnecessary surgery during such abdominal attacks which was fortunately prevented in one of our reported cases (Case 1) by prompt diagnosis before the scheduled surgery.[6] In Case 7, the patient had repeated episodes of abdominal pain and ultrasound abdomen revealed edematous small bowel, ascites: Fluid was of exudative character with normal amylase level. The entire episode would subside spontaneously within 2–3 days with or without conservative general management. On reviewing his past records, it was found that he had undergone various investigations without a definitive diagnosis. In Case 4, the patient had symptoms of laryngeal attacks with change in voice, hoarseness, trouble swallowing, shortness of breath, and wheezing. Prompt recognition of symptoms and effective treatment early-on could prevent morbidity and mortality in such cases, as reported by a study wherein it states that 25%–30% of the patients are estimated to have died because of laryngeal edema before effective treatment was available.[7] Case 6 had a history of genitourinary swelling along with angioedema of eyes and hands. Attacks involving the scrotum or labia have been reported in up to two-thirds of the HAE patients. These attacks may be triggered by local trauma such as horseback riding or sexual intercourse although sometimes no trigger may be evident.[8] Three of our reported cases are females, who generally have a more severe disease course than males because the hormonal changes in females often cause the disease to flare up in menarche, pregnancy, lactation, and menopause. Women also have a higher rate of discontinuing long term androgen therapy because of various side effects.[9] Case 1 had Type III HAE and was on oral contraceptive pills containing estrogen which was stopped and she was advised an alternative for contraception. FFP was used using abdominal attacks. Three of our patients also had associated thyroid dysfunction (hypothyroidism) and one patient had chronic allergic rhinosinusitis, but we could not find any mechanism of association of autoimmune diseases (thyroid disorders) with HAE.[10] Three of these cases gave a positive family history on being asked retrospectively, with similar complaints in the affected family members, ranging from mild to moderate severity. This helped us confirm our diagnosis of HAE.

  Conclusion Top

HAE has catastrophic consequences (mortality 20%–30%). Proper diagnosis and treatment are essential. Many patients of HAE are often misdiagnosed or under-diagnosed, due to the common misconception that all angioedema are histamine mediated. Diagnosis of HAE depends upon a high index of suspicion owing to positive family history, recurrent peripheral swelling, and abdominal or laryngeal attacks. The treatment is targeted at either terminating the acute attacks or at preventing recurrent attacks. Although there is no consensus on ideal management for long-term prophylaxis, some authors favor use of replacement therapy with C1 INH products while others believe that Danazol in the lowest effective dose is still a reasonable and cost-effective prophylactic treatment. When laryngeal edema develops, FFP is used as the second-line treatment along with respiratory support and intubation since C1 INH concentrate is not available in India. Hence, emergency treatment is essential to reduce risk of mortality associated with laryngeal edema in HAE.[10]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Katelaris CH, King N. Hereditary angioedema in Australia: Patients experience and burden of disease. Int Med J 2012;42:9.  Back to cited text no. 1
Lei WT, Shyur SD, Huang LH, Kao YH, Lo CY. Type I hereditary angioedema in Taiwan-clinical, biological features and genetic study. Asian Pac J Allergy Immunol 2011;29:327-31.  Back to cited text no. 2
Kevin TS, Zuraw BL. Recognizing and managing hereditary angioedema. Clevel Clin J Med 2013;80:297-308.  Back to cited text no. 3
Frank MM. Hereditary angiodema: A current state-of-the-art review, VI: Novel therapies for hereditary angioedema. Ann Allergy Asthma Immunol 2008;100:S23-9.  Back to cited text no. 4
Lang DM, Aberer W, Bernstein JA, Chng HH, Grumach AS, Hide M, et al. International consensus on hereditary and acquired angioedema. Ann Allergy Asthma Immunol 2012;109:395-402.  Back to cited text no. 5
Killedar MM, Malani AS. Hereditary angioedema – Presenting as recurrent abdominal pain. Indian J Surg 2011;73:444-6.  Back to cited text no. 6
Baliga M, Ramanathan A, Bhambar RS. Angioedema triggered by pulp extirpation – A case report. Oral Maxillofac Surg 2011;15:253-5.  Back to cited text no. 7
Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med 2002;346:175-9.  Back to cited text no. 8
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med 2006;119:267-74.  Back to cited text no. 9
Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001;161:714-8.  Back to cited text no. 10


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