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PubMed1982

[Clinical features, pathogenesis, and therapy of hereditary angioneurotic edema (author's transl)].

The hereditary angioneurotic edema is probably a more frequent disease than presumed until now. It is inherited as an autosomal dominant trait, and is due to diminished or functionally deficient C1 esterase inhibitor. Family history is negative in cases of spontaneous mutations. Two thirds of the patients are already affected in infancy with peripheral edema, facial edema, abdominal symptoms and/or edema of the glottis occuring spontaneously or secondary to trauma. Recently the prognosis has become better due to early diagnosis and the possibility of substitution therapy with C1 esterase inhibitor. A long-term prophylaxis may be achieved with synthetic androgens.

Adolescent↗

PubMed1976

Hereditary angioedema: the clinical syndrome and its management.

Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C1 esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 30%.

Adolescent↗

PubMed2002

Pathways for bradykinin formation and inflammatory disease.

Bradykinin is formed by the interaction of factor XII, prekallikrein, and high-molecular-weight kininogen on negatively charged inorganic surfaces (silicates, urate, and pyrophosphate) or macromolecular organic surfaces (heparin, other mucopolysaccharides, and sulfatides) or on assembly along the surface of cells. Catalysis along the cell surface requires zinc-dependent binding of factor XII and high-molecular-weight kininogen to proteins, such as the receptor for the globular heads of the C1q subcomponent of complement, cytokeratin 1, and urokinase plasminogen activator receptor. These 3 proteins complex together within the cell membrane, and initiation depends on autoactivation of factor XII on binding to gC1qR (the receptor for the globular heads of the C1q subcomponent of complement). There is also a factor XII-independent bypass mechanism requiring a cell-derived cofactor or protease that activates prekallikrein. Bradykinin is degraded by carboxypeptidase N and angiotensin-converting enzyme. Angioedema that is bradykinin dependent results from hereditary or acquired C1 inhibitor deficiencies or use of angiotensin-converting enzyme inhibitors to treat hypertension, heart failure, diabetes, or scleroderma. The role for bradykinin in allergic rhinitis, asthma, and anaphylaxis is to contribute to tissue hyperresponsiveness, local inflammation, and hypotension. Activation of the plasma cascade occurs as a result of heparin release and endothelial-cell activation and as a secondary event caused by other pathways of inflammation.

Anaphylaxis↗

PubMed2005

Emergency treatment of acute attacks in hereditary angioedema due to C1 inhibitor deficiency: what is the evidence?

Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase-inhibitor (C1-INH) and is characterised by skin swelling, abdominal pain and episodes of upper respiratory tract obstruction. Oedema of the larynx can result in rapid asphyxiation and requires emergency treatment. Three treatment options for emergency treatment of HAE are reviewed: fresh frozen plasma, solvent/detergent-treated plasma and C1-INH concentrate. It is concluded that while all three treatment options are theoretically effective in the emergency treatment of HAE, C1-INH is the treatment of choice.

Acute Disease↗

PubMed1986

Immunoregulatory disorders associated with hereditary angioedema. II. Serologic and cellular abnormalities.

Hereditary angioedema is defined biochemically by a deficiency in the functional activity of the inhibitor of Cl, Cl esterase inhibitor (Cl INH). Deficiency of this regulator of the early classic pathway of complement results in chronic activation of this cascade with a resultant deficiency of C4 and C2. Ninety-seven patients with either complicated (associated with autoimmune disorders) or uncomplicated hereditary angioedema were evaluated for laboratory evidence of immunoregulatory defects. Specific cellular and humoral abnormalities were found and included increased mean total lymphocyte counts, increased mean Leu 4+ (total) and Leu 3+ (helper) T cells, an increased mean Leu 3/Leu 2 (helper/suppressor T cell) ratio, polyclonal B cell activation, and evidence of circulating immune complexes. C4 functional titers were negatively correlated with percent Leu 3+ cells and absolute Leu 3+ cell numbers. We failed to detect any evidence of immune deficiency in this population, and yet a statistically significant number of patients demonstrated elevated levels of antibodies to Epstein-Barr virus antigens when patients were compared to a control group. Thus, early classic complement pathway activation and/or partial complement component deficiency may effect T cell subpopulations and B cell activation. However, additional predisposing factors (e.g., genetic or viral) appear necessary for the development of a particular autoimmune disease in hypocomplementemic patients.

Adolescent↗

PubMed1995

[Life threatening angioedema caused by acquired C1 inhibitor deficiency associated with paraproteinemia and livedo racemosa].

A 61-year-old patient with life-threatening angioneurotic oedema was found to have an acquired C1-inhibitor (C1-INH) deficiency. In addition to lowered serum levels of C1-INH (both protein concentration and enzymatic activity), C2, C4 and CH50, which are characteristic for the hereditary form of angioneurotic oedema, markedly lowered C1q was found, which is typical for the acquired form. There were no antibodies against C1-INH. Repeated thorough examination disclosed no neoplasm, though the presence of neoplasm has often been reported to be associated with the acquired C1-INH deficiency. However, the patient showed persistent paraproteinaemia and paraproteinuria and developed livedo reticularis. Treatment with danazol resulted in a rise of the complement fraction levels and cessation of angioneurotic oedema. Paraproteinaemia and livedo reticularis persisted unchanged.

Angioedema↗

PubMed2001

Hereditary angioedema first apparent in the ninth decade during treatment with ACE inhibitor.

BACKGROUND: Hereditary angioedema ordinarily manifests itself in childhood. The development of angioedema in this disease and as a side effect of angiotensin-converting enzyme inhibitor treatment is caused by similar mechanisms. METHODS: We report a case of female patient, diagnosed with hereditary angioedema at age 90, who experienced the first attack 8 years earlier during angiotensin-converting enzyme inhibitor use. CONCLUSIONS: This patient presented with her first episode of hereditary angioedema at the oldest age ever reported. A careful family history, especially for angioedema, should be taken in patients of all ages before initiating treatment with angiotensin-converting enzyme inhibitor.

Aged↗

PubMed2003

How do we treat patients with hereditary angioedema.

Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.

Acute Disease↗

PubMed1991

[Hereditary angioedema, a rare cause of recurrent abdominal pains. A report of 2 clinical cases and comments of a general nature].

Two clinical cases of recurrent abdominal pain are reported. These led to the unusual diagnosis of hereditary angioedema due to deficiency of C1 esterase inhibitor (C1-INH). The difficulties of identifying this genetic disease were caused by the variability of its clinical expression: the alteration of an autosomal dominant gene triggers angioedema attacks that may strike the cutaneous, gastroenteric and respiratory apparatus with differing intensity. Various subjects suffering from hereditary angioedema were found in the genealogical trees of the two patients, but all had extraintestinal symptoms of very variable intensity. Measurement of C4 and C1-INH made it is possible to identify in the first family a functional defect of C1 esterase inhibitor and in the second a quantitative defect in the same inhibitor.

Abdominal Pain↗

PubMed1989

Inherited C1 inhibitor deficiency.

The paper reports our experience of a 15-year follow-up of 179 patients with hereditary angioedema (HAE). The disease is transmitted as an autosomal dominant trait and two variants have been described: type I characterized by functional and antigenic C1-inhibitor (C1-INH) deficiency and type II with normal or upper normal C1-INH antigenic levels but no functional activity. The clinical picture is characterized by self-limiting bouts of swelling in the subcutaneous and/or mucous tissues. Data about frequency, localization and possible triggering factors of HAE attacks are reported. Analysis of genomic DNA from our patients using a C1-INH cDNA probe demonstrated the presence of restriction fragment length polymorphisms tightly linked with the disease in a minority of them. Data concerning prophylaxis and treatment of HAE attacks are also shown.

Angioedema↗

PubMed1985

The change in C3b receptors on erythrocytes from patients with systemic lupus erythematosus.

A deficiency of C3b receptors (CR1) on erythrocytes from patients with systemic lupus erythematosus (SLE) has already been reported and assumed to be one of the causes of the impaired immune complex clearing function found in these patients. In the present study, we developed a functional assay to quantify the amount of CR1 on human erythrocytes. Sample erythrocytes were reacted with tetanus toxoid-anti-tetanus toxoid immune complexes (IC) in the presence of complement. The amount of CR1 was expressed as the amount of IC bound to sample erythrocytes. Determination of CR1 showed a decrease in erythrocytes from patients with SLE, rheumatoid arthritis and other connective tissue diseases. The activity of CR1 in erythrocytes from patients with SLE changed in parallel with complement activity and also reflected the clinical status of two of three patients. These results imply that the reduction of CR1 found in SLE patients might be cause not only by hereditary factors but by unknown factors that influence the amount or function of CR1.

Adult↗

PubMed2003

Acquired C1-esterase inhibitor deficiency: a rare cause of episodic acute abdominal pain and ascites.

C1-esterase inhibitor deficiency is a rare yet classic medical cause of acute abdominal pain mimicking a surgical emergency. A hereditary form and a very rare acquired form of the disease exist, and both give rise to a similar clinical syndrome despite a different pathogenic mechanism. We describe a typical case of acquired C1-esterase inhibitor deficiency in a 65-year-old woman presenting with recurrent acute abdomen and ascites who had undergone two negative surgical interventions before diagnosis was eventually established. Both the diagnostic and therapeutic approach to this rare condition should be known by emergency physicians for two reasons: (1) it may present as an acute abdominal emergency resulting in unnecessary surgical intervention; and (2) it may cause life-threatening upper airway obstruction as a result of laryngeal oedema.

Abdominal Pain↗

PubMed1985

Elevated plasmin-alpha 2-antiplasmin complex levels in hereditary angioedema: evidence for the in vivo efficiency of the intrinsic fibrinolytic system.

The contact activation and fibrinolytic systems were assessed in 5 patients with hereditary angioedema (HAE). Reductions in F XII levels and increase in kallikrein-like activity in some patients indicated activation of the contact (intrinsic) system of coagulation. A great increase in plasmin-alpha 2-antiplasmin complex in all subjects indicated that in this disease, there is a constantly ongoing fibrinolysis. Since C1-inhibitor, the deficient protein in HAE, is a poor inhibitor of the well-known extrinsic (tissue-type) plasminogen activator, but the major inhibitor of the contact activation system and a related in vitro phenomenon termed intrinsic fibrinolysis, our data show that this fibrinolytic system is also sometimes operating efficiently in vivo. Furthermore, the known clinical data on HAE are compatible with a role of intrinsic fibrinolysis in the pathophysiology of this disease.

Angioedema↗

PubMed1998

Molecular basis of hereditary C1q deficiency.

Complete selective deficiencies of the complement component C1q are rare genetic disorders which are associated with recurrent infections and a high prevalence of lupus erythematosus-like symptoms. The improvements in molecular biology techniques have facilitated the analysis of such genetic defects to a great extend. To date the basis of C1q deficiencies from 13 families have been studied at the genetic level. In each case single base mutations leading to either termination codons, frame shift or amino acid exchanges were thought to be responsible for these defects as no other aberrations were found. In addition to DNA analysis, conventional immunochemical and biochemical methods have contributed substantially to the elucidation of the structural and functional requirements of this complex macromolecule. The present article reviews the different types of C1q defects in regard to structure and function whereas a detailed presentation on the clinical aspects of C1q deficiencies will be given in this issue of the Journal (by WALPORT, DAVIES and BOTTO).

Amino Acid Substitution↗

PubMed1994

Hereditary C1q deficiency and systemic lupus erythematosus.

We describe a 27-year-old women with systemic lupus erythematosus, C1q deficiency and cytomegalovirus retinitis. She suffered from severe SLE, with cutaneous and CNS involvement, and died of CNS disease aged 28. Review of 29 other published cases of C1q deficiency shows that SLE in these patients is often severe (five with CNS disease, ten with glomerulonephritis). The results of autoantibody studies in this and another patient with C1q deficiency and SLE are presented--both patients had autoantibodies to the extractable nuclear antigens, Sm, RNP and Ro, and one patient had high titres of antibodies to dsDNA. One of the patients had previously been treated with fresh frozen plasma, and antibodies to C1q were present in his serum. Homozygous C1q deficiency is associated with a very high prevalence of severe SLE with the full panoply of autoantibodies characteristic of this disease.

Adult↗

PubMed2001

Sleep-disordered breathing and respiratory failure in acid maltase deficiency.

BACKGROUND: Sleep-disordered breathing (SDB) and respiratory failure (RF) are complications of acid maltase deficiency (AMD), a rare hereditary myopathy. OBJECTIVE: To define the relationship between lung and respiratory muscle function, to establish incidence and patterns of SDB, and to determine daytime predictors of SDB. METHODS: Sitting and supine lung and respiratory muscle function tests were obtained in 27 subjects with juvenile and adult AMD (aged 39 +/- 19 years) and compared with outcomes of polysomnography. RESULTS: Ventilatory restriction was present in 17/27 subjects. Inspiratory vital capacity (IVC) correlated (p < 0.005) with peak inspiratory muscle pressure (PIP, R = 0.61), respiratory muscle strain (P(0.1)/P(0.1max), R = -0.68), and gas exchange by day (PaO(2): R = 0.71; PaCO(2): R = -0.64) and night (SaO(2): R = 0.73; P(tc)CO(2): R = -0.75). Diaphragm weakness (DW) was present in 13 subjects, 10 of whom had hypercapnic RF (PaCO(2) 65 +/- 7 mm Hg), and was associated with longer disease course. SDB was found in 13 subjects, 12 with DW. It was characterized by REM-sleep hypopneas that, as ventilatory restriction worsened, were complemented by hypoventilation (P(tc)CO(2) > 50 mm Hg) first in REM sleep, then in non-REM sleep (p < 0.005). SDB was predicted by DW (sensitivity 80%, specificity 86%) and nocturnal hypoventilation by IVC < 40% (sensitivity 80%, specificity 93%). Noninvasive ventilation, instituted for daytime respiratory failure or nocturnal hypoventilation, normalized daytime and nocturnal gas exchange (p < 0.005). CONCLUSION: Vital capacity correlates with respiratory muscle function in AMD. Diaphragm weakness is the major cause of SDB and RF. SDB and nocturnal hypoventilation are predictable from daytime function tests.

Adolescent↗

PubMed1986

[Familial studies of systemic lupus erythematosus. HLA markers and complotypes].

Particular susceptibility to systemic lupus erythematosis (SLE) could be due to a certain alleles of class I, II or III of the major histocompatibility complex (MHC). The existence of total hereditary deficiencies of factor 2 or 4 of the complement in this syndrome suggests the presence of silent alleles which could conceivably play a determining role in the appearance of SLE. In this study, the HLA haplotypes and complotypes (C2, C4, Bf) were determined in 20 individuals suffering from SLE, and compared with 108 healthy, genotyped individuals. The results obtained showed a significant increase in the frequency of C4 BQ0 in patients compared with that found in controls (chi 2 = 12.27, p less than 0.001, Relative Risk = 3.78), and confirm the HLA association, DR3/SLE (chi 2 = 5.45, p less than 0.02, RR = 2.53).

Adult↗

PubMed2006

Mechanism of angioedema in first complement component inhibitor deficiency.

Since shortly after the discovery that hereditary angioedema resulted from deficiency of first complement component (C1) inhibitor, the characterization of the mediator of angioedema has been a major goal. However, because C1 inhibitor regulates activation of both the contract and complement systems, identification of the mediator was not immediately accomplished. For a number of years, some studies appeared to indicate involvement of one system, whereas other studies suggested involvement of the other. However, the vast majority of the evidence accumulated over the past years indicates quite clearly that the major mediator is bradykinin. Therefore, unregulated contact system activation is the defect that leads directly to the development of angioedema.

Angioedema↗