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Monday, February 06, 2006

Angioedema and Complement 1 (C1) Inhibitor

Angioedema and Complement 1 (C1) Inhibitor


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Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate.

January 2006
Nielsen EW, Gramstad S.

Department of Anesthesiology, Nordland Hospital and University of Tromso, Tromso, Norway.


Up to seven in every 1000 patients experience angioedema from angiotensin-converting enzyme (ACE) inhibitors, even after many years of use. In 2003, every 20th Norwegian used an ACE inhibitor.

Case report:

A 61-year-old woman with chronic obstructive pulmonary disease and a past acute myocardial infarction had used 7.5 mg of ramipril daily for the past 7 years. She also used acetylsalicylic acid, simvastatin, theophylline and salmeterol. One night she woke up with edema of the tongue. On hospital arrival, 250 mg of hydrocortisone and 5 mg of dexchlorpheniramine were given intravenously (i.v.) and 0.3 mg of epinephrine was given subcutaneously (s.c.). The edema of the tongue progressed over the next 8 h and made the tongue protrude. Fiberscopy revealed glassy edema of the arytenoids. Inspiratory stridor was heard and the patient could not speak. She became increasingly uneasy and restless. Berinert((R)) complement 1 (C1) inhibitor concentrate (1500 units) was administered i.v. Over the following 20 min, stridor gradually subsided, the patient calmed and she was able to talk.


ACE inhibitor-provoked angioedema shares many clinical features with hereditary angioedema (HAE), including a limited effect of steroids, antihistamines and epinephrine. HAE, caused by excess bradykinin formation as a result of C1 inhibitor deficiency, usually has its laryngeal edema effectively reversed by C1 inhibitor in less than 0.5 h. Although patients experiencing ACE inhibitor-provoked angioedema have normal C1 inhibitor values, as in our patient, excess bradykinin is probably important as ACE breaks down bradykinin. It is unknown why ACE inhibitor-provoked angioedema appears in some and sometimes after many years of use


We believe that C1 inhibitor was effective in reversing the ACE inhibitor-induced angioedema in our patient.

PMID: 16451161

[PubMed - as supplied by publisher]


Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations.

Feb 2006

Kang HR, Yim EY, Oh SY, Chang YS, Kim YK, Cho SH, Min KU, Kim YY.

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.


C1 esterase inhibitor (C1INH) plays a key role in the classical pathway of the complement cascade. Mutations in this gene cause a decreased level of antigenic (type I hereditary angioedema, HAE) or functional (type II HAE) C1INH.


To find novel mutations in C1INH and evaluate the expression of C1INH gene in HAE patients.


Direct sequencing mutation analysis was performed for genomic DNA from three unrelated families (14 HAE patients and 18 family members). Genomic DNA from one family was also analyzed for larger genomic rearrangements, using Southern blotting analysis. We used real-time quantitative polymerase chain reaction (PCR) to evaluate C1INH mRNA expression level.


Four mutations in exons (2311 T-->C, 14 034 G-->A, 16 830 G-->A, and 16 979-16 980 G insertion) and four in introns (738 G-->A, 8531 A-->G, 14 254 A-->G, and 14 337-14 378 TT deletion) were found. Interestingly, all of the nine patients in one family share the same mutation of Gly345Arg (14 034 G-->A) in the seventh exon. In another family, a single base mutation near the splice site (14 254 A-->G) was found in all of the three patients. In the last family, although a significant mutation was not found by direct sequencing, patients showed an abnormal 16 kb fragment in addition to the normal allele (21 kb Bcl I fragment). The C1INH mRNA expression of HAE patients in two families was not significantly different compared with that of normal controls.


The two novel exonal mutations (G-->A and A-->G) and one large gene deletion were associated with the clinical phenotypes of HAE. Considering the normal C1INH mRNA levels but below normal protein levels in two families, their phenotypes would be associated with the post-translational defect.

PMID: 16409206

[PubMed - in process]


Recombinant human C1-inhibitor is effective in the treatment of acute attacks of hereditary angioedema--case report

Porebski G, Bilo B, Obtulowicz K, Obtulowicz P, Nuijens J.

Zaklad Alergologii Klinicznej i Srodowiskowej, Collegium Medicum Uniwersytetu Jagiellonskiego, Krakow.

Hereditary angioedema (HAE) is a rare condition, resting on attacks of edema in various localizations, potentially life-threatening if in facial, laryngeal, pharyngeal or gastrointestinal area. The disease is caused by deficiency or impaired activity of C1 inhibitor, therefore C1 inhibitor infusion is the the essential treatment and the only efficient method in an acute attack of HAE. Nowadays C1 inhibitor applied in our patients is obtained from human plasma, what restricts the availability of the drug and carries relevant risks. After many years of research it came to the synthesis of the recombinant protein with features of human C1 inhibitor. Its first usage in Poland took place-in two HAE patients with severe edema in 2004. The course and efficiency of this treatment is reported in the paper. Recombinant human C1 inhibitor occurred efficient and safe in presented case of severe angioedema.

Publication Types:
Case Reports

PMID: 16334540

[PubMed - indexed for MEDLINE]


Acquired C1-inhibitor deficiency in a patient with systemic lupus erythematosus: a case report and review of the literature.

Nettis E, Colanardi MC, Loria MP, Vacca A.

Department of Medicine, Immunology and Infectious Diseases, Service of Allergy and Clinical Immunology, University of Bari Medical School, Bari, Italy


The C1-inhibitor (C1-INH) is an important member of the serpin family which inhibits the first component of the human complement system and controls contact activation of the coagulation and kinin system. An acquired form of C1-INH deficiency was recognized and classified as type I, which is characterized by accelerated catabolism of C1-INH, whereas type II is defined by the presence of an autoantibody directed against the C1 inhibitor molecule. This study reports the case of a 32-year-old woman with systemic lupus erythematosus (SLE) who experienced recurrent angioedema because of an acquired C1-INH deficiency. The relevant literature is reviewed.

PMID: 16313255

[PubMed - in process]


C1 inhibitor: molecular and clinical aspects.

Cicardi M, Zingale L, Zanichelli A, Pappalardo E, Cicardi B.

Department of Internal Medicine, San Giuseppe Hospital, University of Milan, Milan, Italy.
C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

PMID: 16267649

PubMed - in process]


A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema.

van Doorn MB, Burggraaf J, van Dam T, Eerenberg A, Levi M, Hack CE, Schoemaker RC, Cohen AF, Nuijens J.

Centre for Human Drug Research, Leiden, The Netherlands.



Hereditary angioedema (HAE) is a congenital disorder with recurrent attacks of localized swelling of submucosal tissue, subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor (C1 esterase inhibitor [C1INH]).


We sought to evaluate the effects of recombinant human C1INH (rhC1INH) isolated from the milk of transgenic rabbits in 12 asymptomatic patients with HAE.


rhC1INH was intravenously administered at doses of 6.25 to 100 U/kg on 2 occasions.


rhC1INH appeared safe and was well tolerated. The course of functional C1INH in plasma showed a full initial recovery (dose-normalized maximum concentration of about 0.02 U/mL/U/kg) and a dose-dependent clearance of rhC1INH. After infusion of rhC1INH at 100 U/kg, a clearance of approximately 13 mL/min, a half-life of approximately 3 hours, and a volume of distribution of approximately 3 L were observed. Infusion at this dose led to functional C1INH levels in plasma of at least twice the normal level for about 2 hours and greater than 0.4 U/mL for about 9 hours. rhC1INH displayed dose-dependent biologic activity by increasing the C4 level, which was about 2-fold at 12 hours after rhC1INH at 100 U/kg, and decreasing levels of cleaved C4.


The observed safety profile and biologic activity of rhC1INH warrants further clinical studies to assess its efficacy in treating HAE attacks.

Publication Types:Clinical Trial Clinical Trial, Phase I

PMID: 16210064

[PubMed - indexed for MEDLINE]