Angioedema in a Patient with Underlying Lymphoproliferative Disorder

A 61-year-old female presented to the emergency department for sudden tongue swelling with difficulty talking and swallowing. She received epinephrine and was admitted to the intensive care unit (ICU). Swelling resolved within a few hours after treatment with diphenhydramine and steroids. The patient did not require intubation. Subsequent work-up showed reduced C1 esterase inhibitor (C1-INH) protein; 13 mg/dL (Reference range: 21-39 mg/dL), C1-INH functional 88% (Normal >=88%), C4c <3 mg/dL (Reference range: 15-57 mg/dL), and C1Q <3.6 mg/dL (Reference range 6.0-8.6 mg/dL). Low C1-INH protein levels, complement C4c and complement C1Q lead to the initial diagnosis of acquired angioedema from C1-INH deficiency. CT scans of chest and abdomen were normal. Comprehensive metabolic panel and complete blood count (CBC) were within normal limits. Coagulation screen showed PT 10.5 sec, International normalized ratio (INR) 0.9, and activated partial thromboplastin time (aPTT) 22.1 sec, fibrinogen 328 mg/dL, and D-Dimer 14,519, ng/mL FEU (fibrinogen equivalent unit). Paraprotein workup showed the presence of IgG lambda paraprotein. Bone marrow examination showed 20% monoclonal lambda plasma cells thus confirming a diagnosis of lymphoproliferative disorder. Such disorders range from monoclonal gammopathy of undetermined significance (MGUS) to non-Hodgkin lymphoma in patients with acquired angioedema.

Angioedema is a common presentation in the emergency department because airway angioedema could be fatal without timely intervention. Each year, angioedema or allergic reactions are associated with approximately one million emergency room visits. However, most of these patients are diagnosed with allergic reactions. Therefore, it is important to investigate causes of angioedema because it can be associated with various conditions including drug induced, acquired, hereditary or idiopathic (Table 1).

Acquired angioedema due to C1-INH deficiency is a rare cause of adult-onset non-urticarial angioedema which could lead to life-threatening laryngeal edema and asphyxiation, similar to those observed in patients with hereditary forms of C1-INH deficiency, but without any family history. The classification of C-1-INH deficiency has been expanded due to discovery of many newly identified genetic variations, all of which appear to result in increased levels of bradykinin causing angioedema. Interestingly, hereditary angioedema, a rare disease, is due to deficiency of functional C1-INH where bradykinin is also the biologic mediator of swelling^,.

Diagnostic criteria of acquired C1-INH deficiency has not been established but such disorder is typically observed in older patients (fourth decade of life or later) with underlying conditions such as malignancy (usually B cell in origin; 30-50%), monoclonal gammopathy (30-50%) and autoimmune disorder (5-10%) which are often undiagnosed during first presentation. Patients with an acquired deficiency produce immune complexes that consume large amounts of C1q and C1 esterase inhibitor, resulting in quantitative and functional deficiencies or both. C1-INH antigen may be low or normal in patients with acquired deficiency. Acquired C1-INH deficiency can be distinguished from inherited deficiency by measurement of C1q and C4 complement levels. Patients with the hereditary disease have normal levels of C1q, while those with the acquired form have low levels. Patients with active attacks of all forms of angioedema will have low C2 and C4 levels due to C1 activation and complement consumption. Bowen et al presented a useful algorithm for diagnosis of acquired C1-INH deficiency. Treatment recommendation are available acute attack and prophylaxis of C1-INH deficiency which may also be applicable to acquired C1-INH deficiency. Recently, Busse et al published guidelines for treatment of angioedema. Avoidance recommendations exists for estrogen, tamoxifen and angiotensin-converting enzyme (ACE) inhibitors. Although our patient responded to antihistamine and steroid therapy, a common therapy is treatment with plasma-derived or recombinant C1-INH.

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