Successful resolution of bowel obstruction in a patient with hereditary angioedema.

Hereditary angioedema (HAE), a rare genetic disorder caused by a deficiency of the C1 esterase inhibitor, leads to an episodic, self-limiting increase in vascular permeability. Related symptoms commonly include recurrent, intractable abdominal pain, vomiting, and/or diarrhea. DX-88 (ecallantide), a 60-amino acid recombinant protein discovered through phage display technology, is a highly specific, potent inhibitor of human plasma kallikrein that has been used successfully in the treatment of patients experiencing acute HAE attacks. This case study involves a 65-year-old woman who presented with severe abdominal pain, cramping, and nausea. The study describes the use of a video obtained by capsule endoscopy for the direct imaging of bowel occlusion in a patient with HAE that resolved upon treatment with DX-88. After administration of DX-88, 80 mg intravenously, abdominal pain and nausea resolved within 30 min. Capsule endoscopy demonstrated a coincident resolution of the bowel wall edema, with a return to normal within approximately 1.5 h of DX-88 administration. This case study demonstrates that DX-88 can produce dramatic clinical benefits in a patient with an acute abdominal HAE attack, resolving both symptoms and pathologic signs. Furthermore, it illustrates the usefulness of videos obtained from capsule endoscopy in identifying the presence of bowel occlusion and demonstrating its subsequent rapid resolution upon administration of DX-88.

The deficiency of C1 inhibitor and its treatment.

In this article, we review the traditional therapies of hereditary angioedema (HAE) that have been used for several years. Some of these therapies were proposed before the definition of the underlying defect and the understanding of the pathogenesis of the disease. We also describe new compounds under investigation at present as potential therapies for HAE. Two of these new therapies (a plasma-kallikrein inhibitor and a bradykinin B(2)-receptor antagonist) have been developed based on the understanding that the pathogenesis of symptoms was mainly due to kallikrein activation and bradykinin release.

Lymphoproliferative disease and acquired C1 inhibitor deficiency.

Angioedema due to acquired deficiency of the C1-inhibitor is a bridging condition between autoimmunity and lymphoproliferation. We report 32 patients with acquired C1 inhibitor deficiency: 23 have anti C1-inhibitor autoantibodies; 13 have monoclonal gammopathies of unknown significance and 9 have non-Hodgkin's lymphoma. Our series suggest that different forms of B cell disorders coexist and/or evolve into each other in acquired angioedema.

Angioedema without urticaria: a large clinical survey.

BACKGROUND: Angioedema without major urticarial flares (hives) is poorly understood. Its causes are diverse, and little is known about its pathogenic mechanisms. We report on our 11 years of experience with this condition and propose a classification of patients affected by angioedema unaccompanied by urticaria. METHODS: From 1993 through 2003 at our outpatient clinic, 929 consecutive patients were examined for recurrent angioedema unaccompanied by urticaria. A detailed history was taken to identify known causes of angioedema, with special attention to external allergenic agents. Each patient underwent a complete physical examination, routine laboratory tests (blood cell count, protein electrophoresis, erythrosedimentation rate, examination of stool for ova and parasites, pharyngeal and urine cultures, sinus and dental radiography, and measurements of antitissue autoantibodies and rheumatoid factor in plasma), and complement parameters (C1 inhibitor, C4 and C1q). Further testing was done when pertinent, based on clinical findings. When all results were negative, response to H1-antihistamine was considered. RESULTS: Angioedema could not be classified in 153 patients who were lost to follow-up (16.4%). Among the 776 cases with adequate data, these types of angioedema were identified: 124 (16%) related to external agents such as a drug, insect bite or foodstuff; 85 (11%) related to treatment with angiotensin-converting enzyme inhibitor; 55 (7%) associated with an autoimmune disease or infection; and 197 (25%) caused by C1 inhibitor deficiency. In the other 315 cases (41%), the etiology was undiscovered: 254 cases (33% of the study sample) were idiopathic histaminergic; 40 (5%) were idiopathic nonhistaminergic; and 21 (3%) had other causes of peripheral or generalyzed edema. INTERPRETATION: Our data indicated that angioedema without urticaria could be classified according to specific clinical and pathogenic characteristics, and we have suggested a work-up for patients experiencing this condition.

Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after switching to a different treatment.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are associated with angioedema episodes that are potentially life-threatening. Few data are available on the outcome of patients reporting this adverse effect when they are switched to another drug. Scattered reports of angioedema associated with angiotensin II receptor blocker (ARB) use question the safety of using these drugs in patients with ACE inhibitor-related angioedema. We describe 64 consecutive patients with ACE inhibitor-related angioedema, the outcome after discontinuing this treatment, and the safety of using ARBs. METHODS: Retrospective analysis of 64 consecutive patients (January 1993 to June 2002) presenting with angioedema onset while receiving treatment with an ACE inhibitor. RESULTS: Patients were recommended to stop ACE inhibitor use, substituting it upon advice of the physician. Fifty-four patients were available for follow-up (median follow-up, 11 months; range, 1-80 months): 26 had switched to an ARB, 14 to a calcium antagonist, and 14 to other antihypertensive drugs. Angioedema disappeared or drastically reduced upon withdrawal of the ACE inhibitor in 46 patients (85%). For the remaining 8 patients, angioedema was due to a cause other than ACE inhibitor use in 2; angioedema persisted independent of the treatment and without apparent cause (idiopathic angioedema) in 4; angioedema persisted after switching to an ARB and disappeared upon its withdrawal in 2. CONCLUSIONS: Stopping ACE inhibitor use without further assessments is a successful measure in the large majority of patients developing angioedema while taking this drug. Only a small percentage of patients with ACE inhibitor-related angioedema continue with this symptom when switched to an ARB.

Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.

Angioedema due to acquired C1-inhibitor (C1-INH) deficiency (also referred to as "acquired angioedema") is a rare, life-threatening disease with poorly defined etiology, therapy, and prognosis. To define the profile of acquired C1-INH deficiency and to facilitate the clinical approach to these patients, we report on 23 patients with acquired C1-INH deficiency followed for up to 24 years (median, 8 yr), and review the literature. We measured C1-INH activity with chromogenic assay and detected autoantibodies to C1-INH by enzyme-linked immunosorbent assay (ELISA). Median age at onset of angioedema was 57 years (range, 39-75 yr). All patients had C1-INH function and C4 antigen below 50% of normal. C1q was reduced in 17 patients. Autoantibodies to C1-INH were present in 17 patients. Long-term prophylaxis of attacks with danazol was effective in 2 of 6 patients, and with tranexamic acid, in 12 of 13 patients. Therapy with C1-INH plasma concentrate was necessary in 12 patients: 9 had rapid positive response and 3 became progressively resistant. Associated diseases at the last follow-up were non-Hodgkin lymphomas (3 patients), chronic lymphocytic leukemia (1 patient), breast cancer (1 patient), monoclonal gammopathies of uncertain significance (13 patients). In 4 patients no pathologic condition could be demonstrated. Compared with the general population, patients with acquired C1-INH deficiency present higher risk for B-cell malignancies, but not for progression of monoclonal gammopathies of uncertain significance to malignancy. Antifibrinolytic agents are more effective than attenuated androgens in long-term prophylaxis. Patients with acquired C1-INH deficiency may be resistant to replacement therapy with C1-INH plasma concentrate.

Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol.

The attenuated androgen Danazol can partially reverse the biochemical defect and prevent angioedema in patients with inherited C1-inhibitor (C1-INH) deficiency (hereditary angioedema, HAE). Though its clinical effectiveness is independent from significant increase of C1-INH plasma levels, its mechanism of action remains unknown. Since angioedema is a local phenomenon, it could be controlled by restoring tissue levels of C1-INH. We measured the expression of C1-INH mRNA in peripheral blood mononuclear cells (PBMCs) of 13 patients with HAE type 1 (seven untreated and asymptomatic, and six on Danazol at the minimal effective dose) and of eight normal controls. mRNA levels were quantitated by computerized optical densitometry of reverse transcriptase-PCR products, normalized for the amount of glyceraldehyde-3-phosphate-dehydrogenase and expressed as percent of normal pooled RNAs. Each determination represented the mean of three separate experiments. Measurement of C1-INH mRNA in two patients before and after 1 month of Danazol 400 mg per day demonstrated a post-treatment increase of 15 and 21%, respectively. When HAE patients and controls were analyzed as groups, C1-INH mRNA levels of patients untreated and asymptomatic (median 73%, range 65-78) were significantly lower (P=0.001) compared to controls (median 101%, range 87-121) and to patients on Danazol (median 91%, range 82-96); the difference among the last two groups was not statistically significant. Our data demonstrate that minimal effective doses of Danazol increase the expression of C1-INH mRNA in PBMC of HAE patients even in the absence of a significant increase of C1-INH plasma levels.

Mechanisms of C1-inhibitor deficiency.

C1 inhibitor (C1-Inh) is a protease inhibitor of the serpin family. It interacts and forms complexes with several serine proteases although not all these interactions were proved to be relevant in vivo. Based on studies in deficient patients, C1-Inh appears pivotal in regulating the activation of complement classical pathway and of contact system. The best recognized consequence of defective C1-Inh function is predisposition to episodes of self-limited, increased vascular permeability (angioedema) that is restricted to three specific sites, which include the subcutaneous space, the gut and the upper airway. Candidate mediator of angioedema is bradykinin, a potent vasoactive peptide, released upon contact system activation. Mutations in C1-Inh structural gene are the most common cause of C1-Inh deficiency and lead to hereditary angioedema. Recurrent angioedema are also seen in the acquired defect of C1-Inh that is due to autoantibodies against this protein or to an associated disease causing accelerated catabolism of C1-Inh. Apart from the profound deficiency of C1-Inh characteristic of angioedema, it has been suggested that, in specific pathologic settings, C1-Inh levels in the low normal range could still represent a significant functional deficiency. Such conditions, as extensively investigated in sepsis, are of great relevance because they open the possibility of using C1-Inh as therapeutic agent in several different diseases.

Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema.

BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) in 2004. OBJECTIVE: To ensure that this consensus remains current. METHODS: In collaboration with the Canadian Network of Rare Blood Disorder Organizations, we held the second Canadian Consensus discussion with our international colleagues in Toronto, Ontario, on February 3, 2006, and reviewed its content at the Fifth C1 Inhibitor Deficiency Workshop in Budapest on June 2, 2007. Papers were presented by international investigators, and this consensus algorithm approach resulted. RESULTS: This consensus algorithm outlines the approach recommended for the diagnosis, therapy, and management of HAE, which was agreed on by the authors of this report. This document is only a consensus algorithm approach and continues to require validation. As such, participants agreed to make this a living 2007 algorithm, a work in progress, and to review its content at future international HAE meetings. CONCLUSIONS: There is a paucity of double-blind, placebo-controlled trials on the treatment of HAE, making levels of evidence to support the algorithm less than optimal. Controlled trials currently under way will provide further insight into the management of HAE. As with our Canadian 2003 Consensus, this 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of HAE was formed through the meeting and agreement of patient care professionals along with patient group representatives and individual patients.

Angiotensin-converting enzyme inhibitor-related angioedema: how to deal with it.

Angiotensin-converting enzyme inhibitor-related angioedema is a well documented condition, which seems to occur in up to 1% of treated patients. It represents a problem for both the clinician and the patient: for the clinician, the diagnosis may be difficult due to its peculiar clinical characteristics, whereas for the misdiagnosed patient the delay prolongs a potentially dangerous situation. If the drug is not discontinued, the attacks tend to become worse and even life-threatening. There are now evidences that increased levels of bradykinin have an important role in the pathophysiology of attacks and, moreover, there are genetic factors that render certain individuals susceptible to angiotensin-converting enzyme inhibitor-related angioedema. In this review, the authors analyse the pathogenetic mechanism, the clinical presentation, the management and future perspectives of research on this condition.

C1 inhibitor gene expression in patients with hereditary angioedema: quantitative evaluation by means of real-time RT-PCR.

BACKGROUND: Hereditary angioedema (HAE) is caused by heterozygous defects in the C1 inhibitor (C1-INH) gene (SERPING1/C1NH). In patients' plasma C1-INH levels range between 5% and 30% of normal levels (ie, far from the 50% expected for an autosomal dominant defect). Most patients have antigenic and functional deficiency (type I HAE), and 15% have reduced C1-INH function but normal to increased antigen because of the presence of a dysfunctional protein (type II HAE). OBJECTIVE: We sought to contribute to the understanding of the pattern of C1-INH gene expression in patients with HAE. METHODS: We used real-time quantitative RT-PCR to measure C1-INH mRNA levels in PBMCs of 57 patients with HAE typed for mutations in the SERPING1/C1NH gene. RESULTS: Thirty-six different mutations were identified in genomic DNA. Compared with healthy control subjects, C1-INH mRNA was significantly and similarly reduced in patients with type I and type II HAE (40% and 47%, respectively; P <.0001). By means of direct sequencing of cDNAs, we found that 74% of patients with type I HAE carrying small mutations presented significant amounts of mutated transcripts at the mRNA level, suggesting that both allelic mRNA products were reduced to approximately 50%. In 4 patients carrying large deletions expected to fully inactivate expression from the mutant allele, C1-INH mRNA was 23% on average compared with that seen in control subjects, confirming that normal mRNA was strongly underexpressed. CONCLUSIONS: These new findings, combined with previous evidence of increased C1-INH consumption, might explain the plasma levels of normal C1-INH that are markedly less than the expected 50%.