Acquired deficiency of the inhibitor of the first component of complement: Report of five additional cases with commentary on the syndrome

doi:10.1016/0091-6749(85)90087-9

Journal of Allergy and Clinical Immunology

Volume 75, Issue 6, June 1985, Pages 640-646

https://doi.org/10.1016/0091-6749(85)90087-9 Get rights and content

Abstract

The association of late onset recurrent angioedema with a deficiency of the inhibitor of the first component of complement (C $1 ̄$ INH)and of the binding subunit of the first component, Clq, defines the syndrome of acquired C $1 ̄$ INH deficiency. The description of five new cases, along with the original two and the 18 others in the literature, brings the total reported cases to 25 and highlights the associated B cell abnormalities that are present in 23 and are of a malignant nature in 19 cases. In three of the five newly reported cases, the occurrence of angioedema, which prompted recognition of the acquired deficiency of C $1 ̄$ INH, Clq, and C4, preceded the delineation of the underlying B cell malignancy by 2 to 3 yr despite efforts to recognize neoplastic disease in two of these patients throughout the interval. Because the acquired C $1 ̄$ INH deficiency reflects increased catabolism rather than impaired biosynthesis, only high-dose attenuated androgens elicit a measurable increment in serum C $1 ̄$ INH. The occurrence of the syndrome with multiple myeloma is noted for the first time.

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These complexes were elevated before treatment, but reverted rapidly to normal values during androgen therapy and remained normal with reduction of dose as long as the patient remained free of symptoms. In addition, attenuated androgens have been shown to prevent symptoms and increase C1-INH plasma levels in non-autoantibody-mediated acquired angioedema (Sheffer et al., 1985). Danazol has been useful in treating other immune-mediated diseases such as Henoch–Schönlein purpura (Lee et al., 1993).
This chapter discusses the danazol therapy. Danazol is a synthetic attenuated androgen that has been used to treat immune-mediated diseases. This drug suppresses the pituitary–ovarian axis. This suppression probably results from a combination of depressed hypothalamic–pituitary response to lowered estrogen production, alteration of sex steroid metabolism, and interaction of danazol with sex hormone receptors. Danazol has weak androgenic activity. Danazol is useful in treating both refractory idiopathic thrombocytopenia purpura (ITP) and autoimmune thrombocytopenia associated with connective tissue diseases. The mechanism of action of danazol in autoimmune thrombocytopenia is unknown. Primary ITP is a common hematologic disorder manifested by immune-mediated thrombocytopenia. An understanding of the natural history of untreated ITP, which is different in children and adults, provides part of the rationale for deciding which patients should be treated. ITP is caused by accelerated destruction of antibody-sensitized platelets.
Acquired Deficiency of the Inhibitor of the First Complement Component: Presentation, Diagnosis, Course, and Conventional Management
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Successful treatment of the underlying disease has been shown to resolve angioedema symptoms and biochemical abnormalities in patients who have acquired C1-INH deficiency. The first such report from Cohen and colleagues [32] has been repeatedly confirmed [4,8,27,33–39], although the details of the responses have demonstrated a wide range of variability. Disappearance of angioedema may be temporary, even without evidence of a relapse of the associated disease [32,35].
A patient with facial and neck swelling, dyspnea, and dysphagia
2005, Annals of Allergy, Asthma and Immunology
Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond
2004, Journal of Allergy and Clinical Immunology
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Like other acquired forms of protein deficiencies, the course of acquired C1-INH deficiency can be related to the course of the underlying disease. The possibility of reversing the biochemical and/or clinical abnormalities of acquired C1-INH deficiency by curing the associated disease was reported by Cohen et al105 and subsequently confirmed.122,132,370-372 However, the response can be temporary, even without evidence of relapse of the associated disease.373
Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.
Clinical and laboratory evaluation of complement deficiency
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Goodpasture's syndrome is another well-studied example of this general paradigm. Acquired angioedema (AAE) is caused by clearance of C1-Inh, either through excessive activation of C1 or other enzymes that react with it or by autoantibodies to the C1-Inh.55–57 Even though its clinical features are indistinguishable from those of HAE, factors such as lack of family history, later age of onset, and the presence of a malignancy (in ∼50%) favor AAE over HAE.40,58
The complement system provides innate defense against microbial pathogens and is a “complement” to humoral (antibody-mediated) immunity. Consisting of plasma and membrane proteins, this proinflammatory system works in part by a cascade involving limited proteolysis whereby one component activates the next, resulting in a dramatic amplification. The overall goal is deposition of complement fragments on pathologic targets for the purposes of opsonization, lysis, and liberation of peptides that promote the inflammatory response. Deficiencies of complement components predispose to infections and autoimmune syndromes. Even though total deficiency of a complement component is rare, patients presenting with certain bacterial infections and autoimmune syndromes, especially SLE, have a much greater incidence of deficiency. This review will summarize the clinical manifestations and pathophysiology of congenital and acquired complement deficiency diseases. We will also present an algorithm for laboratory diagnosis of complement deficiency and discuss current and future therapeutic options.

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^☆: Supported by grants AI-22531, AI-10356, AI-17917, HL-17382, AM-05577, RR-02172, and RR-05669 from the National Institutes of Health.

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Original articleAcquired deficiency of the inhibitor of the first component of complement: Report of five additional cases with commentary on the syndrome☆

Abstract

Clin Immunol Immunopathol

Am J Med

Blood

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

Action of complement in hereditary angioneurotic edema: the role of C'1 esterase

J Clin Invest

Natural control mechanisms of the complement system

Evidence for immune complexes involving antilymphocyte antibodies associated with hypocomplementemia in chronic lymphocytic leukemia (CLL)

Clin Exp Immunol

Angioedema and hypocomplementemia

J Allergy Clin Immunol

Acquired C1 inhibitor deficiencies in lymphoproliferative diseases with serum immunoglobulin abnormalities: a study of three cases

Blut

Treatment of acquired C1 inhibitor deficiency with danazol

Ann Intern Med

Diffuse normolipaemic plane xanthomatosis, an abnormal complement component profile

Clin Exp Immunol

Original article
Acquired deficiency of the inhibitor of the first component of complement: Report of five additional cases with commentary on the syndrome☆