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PubMed2006

Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency.

BACKGROUND: Administration of C1-inhibitor concentrate is effective for prophylaxis and treatment of severe angioedema attacks caused by C1-inhibitor deficiency. The concentrate should be administered intravenously and hence needs to be administered by health care professionals, which might cause considerable delay in treatment and inconvenience for patients. OBJECTIVE: The aim of this study was to investigate the feasibility, efficacy, and safety of on-demand and prophylactic self-administration of C1-inhibitor concentrate in patients with frequent attacks of angioedema. METHODS: Patients with hereditary or acquired C1-inhibitor deficiency who had very frequent angioedema attacks were trained to self-administer C1-inhibitor concentrate. The study consisted of 31 patients using on-demand treatment and 12 patients using prophylaxis with C1-inhibitor concentrate. Mean follow-up was 3.5 years. RESULTS: All patients were capable of self-administering the concentrate, with technical failure rates of self-injection being less than 2%. Times between the onset of the attack and the initiation of relief or complete resolution of symptoms in the on-demand group were significantly shortened (2.2 hours and 7.9 hours, respectively) compared with the situation before the start of self-administration. In the prophylaxis group self-administration of C1-inhibitor concentrate decreased the angioedema attack rate from 4.0 to 0.3 attacks per month. CONCLUSION: Intravenous self-administration of C1-inhibitor concentrate is a feasible and safe option and results in more rapid and more effective treatment or prevention of severe angioedema attacks in patients with C1-inhibitor deficiency. CLINICAL IMPLICATIONS: Self-administration of C1-inhibitor concentrate could be a valuable and convenient treatment modality to prevent or treat angioedema attacks in patients with C1-inhibitor deficiency.

Adult↗

PubMed1995

A murine model for the study of mycotic mastitis.

This study established a murine model for the study of mycotic mastitis. The mammary glands of BALB/c mice were inoculated on the fifth day of lactation with graded doses (10(4), 10(5) and 10(6) cells) of a pathogenic strain of Candida krusei isolated from bovine mastitis. The animals were killed 1, 2, 3, 4 or 5 days after inoculation. In the infected mammary glands, the pathological reaction consisted of primary infiltration with heterophils and mononuclear cells, focal necrosis, formation of microabscesses, epithelial hyperplasia and some fibrosis. The severity of the changes was dose-dependent and increased with time after infection. An increase in the plasma concentrations of complement factors C1, C3c, C4 and C5, factor B and alpha-2-macroglobulin suggested that an acute phase response and activation of the complement system had occurred as a result of the infection.

Acute-Phase Reaction↗

PubMed1999

Hereditary angioedema with gastrointestinal involvement: endoscopic appearance.

We present the first reported case of hereditary angioedema (HAE) with gastric involvement to be successfully evaluated by endoscopy both during and after an attack. A 31-year-old man who had a family history of angioedema was admitted to our hospital with complaints of abdominal pain and swelling of extremities. Computed tomography scan and endoscopy carried out during this attack revealed transient gastrointestinal wall edema which, along with decreased levels of serum C4 and C1 inhibitor, confirmed the diagnosis of HAE with gastrointestinal involvement. During the attack, the gastric mucosa was erythematous and edematous, and parts of its surface bulged into the gastric lumen, resembling a submucosal tumor, as a result of massive submucosal edema. During the healing process, a number of small nodules and raised erosions developed over the entire gastric mucosal surface after healing of prominent gastric edema. Within 55 days, the gastric mucosa had returned to normal. The endoscopic findings for the stomach in HAE have not, to our knowledge, been previously described.

Adult↗

PubMed2000

Detection of C1 inhibitor mutations in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) results from a deficiency in the functional level of C1 inhibitor caused by mutations in the C1 inhibitor gene. The mutations responsible for HAE have been shown to be heterogeneous. OBJECTIVE: Because the identification of C1 inhibitor mutations may depend, in part, on the technique used to screen for mutations, we screened the entire C1 inhibitor coding region to identify mutations in a cohort of patients with HAE. METHODS: By using single-stranded conformational polymorphism analysis, 24 subjects with HAE from 16 different kindreds were screened for C1 inhibitor polymorphisms. C1 inhibitor mutations were identified by sequencing the exons containing identified polymorphisms. RESULTS: All 24 subjects with HAE had identifiable polymorphisms, involving exons 2, 3, 4, 5, or 8. Fourteen different C1 inhibitor mutations were identified: 8 missense, 1 nonsense, 4 frameshift, and 1 small deletion mutations. No large deletions or duplications were found. Nine of the 14 mutations represent newly recognized C1 inhibitor mutations, 6 of which involve exon 4. CONCLUSIONS: Single-stranded conformational polymorphism is an effective approach for identifying new mutations in HAE. Elucidation of the range of C1 inhibitor mutations causing HAE is important for both defining which residues are required for C1 inhibitor secretion or function and providing the basis for future studies to define the relationship between the C1 inhibitor genotype and disease severity.

Angioedema↗

PubMed1990

Complement components and receptors: deficiencies and disease associations.

The complement system, accessory to many immunological functions, consists of a number of interdependent components and receptors. Numerous in vitro approaches have elucidated the biological role of these components and receptors. However, it is the in vivo "natural" experiments that underscore their importance. The phagocytosis and subsequent digestion of pyogenic bacteria is significantly enhanced by the fixation of the third complement component to the bacterial cell wall. Equally important is the intact expression of a receptor (CR3) for the C3b cleavage fragment. Breakdown in this ligand-receptor interaction due to either C3 or CR3 deficiency leads to pyogenic infection. Interestingly, C3-deficient individuals do not demonstrate leukocytic infiltration at the site of infection. Undoubtedly, this is due to the lack of C5 convertase and failure to produce C5a. CR3-deficient individuals, on the other hand, do demonstrate leukocytosis since the third complement component is functional. C3 deficiency is not necessarily a primary lesion and may be secondary to factor I deficiency. In this case, the C3b fragment, along with factor B, acts as a C3 convertase. Inefficient inactivation of C3b, due to factor I deficiency, leads to the uncontrolled consumption of the third component, resulting in C3 deprivation. It appears that phagocytosis by neutrophils and monocytes followed by enzyme-interaction is not sufficient for destruction of the Neisseria organisms. In addition to this leukocyte activity, an intact membrane attack complex, composed of the late complement components C5, 6, 7, 8, and 9, is required for the lysis of these bacteria. This is supported by findings that individuals deficient in late components are highly susceptible to systemic Neisseria infections. Diseases of an autoimmune nature are frequently associated with a deficiency of one of the early complement components C1, C2, or C4 and a deficiency of erythrocytic CR1 receptors as well. This may suggest that proper interaction between a complement fragment of the immune complex with the complement receptor expressed on the erythrocyte is important for proper management and clearance of the complex. Deficiency of the early complement components would prevent the activation of C3 and the fixation of a resulting C3 cleavage product. In this case, erythrocytes would be unable to participate in the transport of the immune complex to the reticuloendothelial system. Instead, tissue deposition of the complex would occur more readily, contributing to the pathologic process. Provided that the early complement cascade were intact, deficiency of erythrocytic CR1 receptors would contribute to the pathologic response for the same reason.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoimmune Diseases↗

PubMed1989

Regulation of C1-inhibitor synthesis by interferons and other agents.

C1-inhibitor (C1-inh) is synthesised and secreted by at least four cell types: hepatocytes, mononuclear phagocytes, fibroblasts and umbilical vein endothelial cells. The production of this protein by monocytes/macrophages and Hep G2 cells has been studied in great detail. Environmental factors alter C1-inh synthesis by these cells. A number of agents which inhibit monocyte C1-inh production (such as histamine, PGE2 C5a des arg and serum treated immune complexes) bind to membrane receptors, activate adenylate cyclase, elevate intracellular cAMP and activate cAMP-dependent protein kinase. Elevation of monocyte cAMP levels is associated with decreased C1-inh secretion by these cells and reduced C1-inh mRNA levels. These changes can be seen within 8 hours of exposure. Stimulation of monocyte C1-inh synthesis occurs after the addition of agents which induce the formation of sodium ion and calcium ion channels, activate the phosphatidyl inositol cycle and activate protein kinase C (immune-complexes, carbamylcholine and phenylephrine). Agents which act directly on protein kinase C (phorbol myristate acetate) also stimulate C1-inh synthesis. Amongst the most potent stimulators of monocyte and Hep G2 C1-inh synthesis are the interferons (Ifns) Ifn alpha, Ifn beta and Ifn gamma. These are known to bind to specific receptors on cells (Ifn alpha and beta binding to Type I Ifn receptors and Ifn-gamma binding to type II Ifn receptors). At least two mechanisms by which Ifn receptor-ligand interaction elicit their effects exist. These are: 1) binding of an activated receptor transducer/regulatory component to specific DNA sequences on Ifn sensitive genes; 2) the activation of protein kinase C and binding of its regulatory components to specific DNA sequences. Ifn alpha, beta and gamma cause a dose related increase in monocyte and Hep G2 cell C1-inh mRNA abundance and protein synthesis. Ifn-gamma is the most potent of the interferons on monocyte C1-inh synthesis. Ifn alpha and beta being less effective but equipotent. These cytokines elicit their maximum effect on monocyte C1-inh synthesis after 1-2 hours treatment. This rapid stimulation of monocyte C1-inh synthesis suggests that this increases the transcription of the C1-inh gene. After removal of Ifns from monocytes the elevated C1-inh mRNA levels subside towards control levels of expression in Ifn alpha and beta-treated cells but remain elevated in Ifn-gamma-treated monocytes. This binding suggests that Ifn-gamma alters the stability of C1-inh mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Hepatocellular↗

PubMed1984

On the role of the C1-esterase inhibitor in cold urticaria.

Plasma samples from 20 patients with acquired cold urticaria were studied. The C1-esterase inhibitor activity was found to be low, but the total C1-esterase inhibitor concentration was normal. Prekallikrein, plasmin-alpha 2-antiplasmin complex, and kallikrein-like activity were also found to be within normal limits. Cold-promoted activation of coagulation factor VII occurred in 45% of the patient plasmas and resulted in a considerable drop in C1-esterase inhibitor activity.

Adolescent↗

PubMed1995

Factor VIIa in patients with C1-inhibitor deficiency.

In hereditary angioedema (HAE), normal C1-inhibitor (C1-INH) is low and the contact system activated. Recently, the findings of a tissue factor mutant selectively deficient in promoting the conversion of FVII to FVIIa, but with retained cofactor for FVIIa, made it possible to examine reliably the pre-existing content of FVIIa in HAE patients. This was of interest as FXIIa (mainly inhibited by C1-INH) is able to activate FVII directly. FVIIa in 21 remission HAE patients were within normal limits but nearly doubled as compared to their 23 normal siblings (p = 0.0017). Cold promoted activation of FVII (CPA) (common clot assay) was displayed in plasma of all 5 untreated patients (C1-INH function < 35%), but not in plasma of 2 patients treated prophylactically with danazol (C1-INH function about 40%). These results suggest that there is a minute, yet significant activation of FVII in patients with C1-INH deficiency.

Angioedema↗

PubMed1982

Exacerbation of a lupus-erythematosus-like syndrome during treatment of non-C1-esterase-inhibitor-dependent angioedema with danazol.

A 70-yr-old man presented with symptoms of angioedema and a lupus erythematosus-like syndrome. Because initial studies showed a functional deficiency of C1 esterase inhibitor and low C4 levels, he was treated with danazol, an attenuated androgen that has proven to be effective in the treatment of angioedema associated with C1 esterase inhibitor deficiency. After treatment, the patient's C4 levels returned to normal and his angioedema resolved, but concurrently he experienced clinical and laboratory exacerbations of his lupuslike illness. Specifically, on two occasions after danazol treatment he developed arthralgias, myalgias, hematuria, and pleuritic chest pain, accompanied by increased titers of antinuclear antibodies and circulating immune complexes. Serum testosterone levels were decreased during these episodes. Because treatment with danazol was temporally associated with recurrent exacerbations of a lupuslike illness and low serum testosterone levels, we believe that this case is an example of sex hormonal modulation of a lupuslike disease in man.

Aged↗

PubMed2006

Hereditary angioedema managed with low-dose danazol and C1 esterase inhibitor concentrate: a case report.

BACKGROUND: Hereditary angioedema (HAE) is a rare life-threatening disease that can occur in pregnancy. CASE: A nulliparous woman was diagnosed as having HAE at 22 weeks of gestation after a series of symptomatic episodes. Following an initial course of C1 esterase inhibitor (C1EI) therapy for an acute episode of HAE, she was treated with danazol for prophylaxis. Danazol did not prevent recurrence of symptoms, its use was discontinued after six weeks. Thereafter, the patient was treated exclusively with C1EI at weekly intervals for exacerbations of her HAE. At 37 weeks' gestation, she delivered healthy 3050 g female neonate. At the time of discharge the female neonate had no signs of virilization or congenital anomalies. CONCLUSION: Low dose danazol was ineffective in treating this woman's HAE in pregnancy. The use of C1EI in pregnancy is associated with good outcomes.

Adult↗

PubMed1997

Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds.

OBJECTIVES: Hereditary angio-oedema (C1-inhibitor deficiency) is a disease with protean manifestations which is often misdiagnosed initially. The purpose of this study was to delineate the clinical spectrum and course of this potentially life-threatening disease. SETTING: Ten members of two unrelated affected kindreds were repeatedly hospitalized in our service with attacks of angio-oedema. Among the 271 members of the two kindreds 69 were identified who reported typical attacks. DESIGN AND SUBJECTS: Detailed information on the clinical course and laboratory data (C1-inhibitor concentration and activity, C4 concentration) were obtained from 59 of the 69 affected subjects. RESULTS: C1-inhibitor concentration and activity were low in all affected patients. The disease had become manifest by age 30 years in 98%. Most patients suffered from attacks of subcutaneous swellings and abdominal pain, and half of the patients have had attacks affecting the airways. The frequency of attacks ranged from less than one to over 26 per year. Forty-two per cent had to be hospitalized at least once. Four have died of acute airway obstruction. Thirty-eight attacks in 10 patients hospitalized in our service were all treated successfully with fresh frozen plasma or with C1-inhibitor concentrate. Trauma, stress, insect stings and foodstuff were triggering factors, but the majority of attacks occurred without an identifiable trigger. Oral contraceptives and pregnancy led to worsening of symptoms. Nonetheless, all 36 pregnancies reported were carried to term. Twenty-five patients were on continuous treatment with attenuated androgens or tranexamic acid, but only seven were free of attacks in the year preceding the survey. CONCLUSION: Hereditary angio-oedema is an autosomal dominant disease with great variability of clinical expression and severity, even within a single kindred. It often goes unrecognized over years, and it may lead to death if, in case of impending airway obstruction, specific therapy is not instituted.

Acute Disease↗

PubMed1992

C1 inhibitor hinge region mutations produce dysfunction by different mechanisms.

Heterozygosity for a mutant dysfunctional C1 inhibitor protein, a member of the serine proteinase inhibitor (serpin) superfamily, results in type II hereditary angioneurotic oedema. We identified a "hinge" region mutation in C1 inhibitor with a Val to Glu replacement at P14 Val-432. Recombinant C1 inhibitors P10 Ala-->Thr and P14Val-->Glu did not form stable complexes with fluid phase C1s or kallikrein. The P14 Val-->Glu mutant, however, was cleaved to a 96K form by C1s, while the P10 Ala-->Thr mutant was not. The recombinant P10 mutant also did not complex with C1s, kallikrein or beta-factor Xlla-Sepharose. The two mutations, therefore, result in dysfunction by different mechanisms: in one (P14 Val-->Glu), the inhibitor is converted to a substrate, while in the other (P10 Ala-->Thr), interaction with target protease is blocked.

Alanine↗

PubMed1982

Purification and characterization of human C1-esterase inhibitor.

A new purification method for C1-esterase inhibitor is described, which is essentially a three-step procedure: precipitation with poly(ethylene glycol), chromatography on DEAE-cellulose and hydrophobic interaction chromatography on hexyl-Sepharose. The final product is a single-chain glycoprotein with a molecular weight of about 100 000 and NH2-terminal asparagine. The molecule is fully active as judged by complex formation with C1s. Two of its three disulphide bridges can be easily reduced and S-carboxymethylated under non-denaturing conditions without loss of activity. However, at high dithioerythritol concentration the third disulphide bridge is also cleaved and accompanied by loss of the activity, indicating that this disulphide bridge is involved in maintaining the conformation around the reactive site in the inhibitor.

Amino Acids↗

PubMed1998