INTRODUCTION
The initial descriptionof hereditary angioedema by Quincke (1) in 1882 included featuressuch as episodic edema of subcutaneous tissue and/or mucosa thataffect the face, extremities, genitalia, dorsal region, andabdomen. In the abdomen, HA can simulate acute surgical conditions.Renal colic, vomiting and/or diarrhea are often observed in somepatients. The main expression of HA is acute laryngeal edema anddeath by asphyxia. In children under the age of 10, intestinalcolic and edema of the extremities are the most frequentmanifestations.
Patients with HA haveepisodes of local swelling, usually affecting the face,extremities, upper airway, and gastrointestinal tract. Itfrequently causes recurrent abdominal pain (with or withoutascitis). Early diagnosis is important because the disease haspotentially life-threatening complications.
HA complications observedin our group were: death of a 10 year-old child from laryngealasphyxia, membrane-proliferative glomerulonephritis in an 8year-old, and death of a patient with Type III HA from tonsillaryedema.
Intestinal colicfrequently appears alone or associated with other manifestations ofedema.
The trigger events arenot clear; they may be traumatic, psychological, or related withdrug administration or menstruation. These acute episodes tend tolast 48 to 72 hours and often remit spontaneously. Patients arecommonly treated with steroids or antihistaminic drugs. As a resultof the disappearance of symptoms, the correct diagnosis of HA maybe delayed (diagnostic error). Symptoms vary between individualsand families and within the same family (2) (clinicalpolymorphism). We have observed asymptomatic disease in severalpatients 60 years-old or older.
ETIOLOGY,PATHOGENESIS, AND INHERITANCE
The disease ishereditary, as first observed by Osler (3) in 1889. Inheritance isautosomal dominant with incomplete penetration. This characteristicobliges us to examine the family tree thoroughly. In our experiencewith hereditary angioedema, mutations are spontaneous in 37% andthree is no family history of the disease (4) (table I).
| Table I Inheritance pattern in 16 family groups of 88patients with hereditary angioedema: 55 men, 33women | |
| (19 under the age of 10 years). The average age at time ofdiagnosis was 23 years | |
| No. of families | |
| Two or moregenerations | 10 |
| Spontaneous with secondHA generation | 2 |
| Spontaneous with no HAgeneration | 1 |
| Spontaneous with nooffspring | 3 |
The disease may occur ingrandparents and be inherited by grandchildren. "Spontaneous" HAwas transmitted hereditarily in 6 families in our series. Recently,the C1 inhibitor gene was cloned and mapped to chromosome 11,making it possible to demonstrate that this gene is abnormal inpatients with hereditary angioedema and that different mutation canbe responsible. Most of the genetic abnormalities are pointmutations or small deletions and insertions. Major generearrangements, with partial deletions or duplications, account for15% to 20% of mutations and are usually related to clusters ofrepetitive DNA sequences, known as Alu repeats. These repeats,which represent processed forms of 7SL RNA genes, are present inthe C1 inhibitor gene as well as in many others and facilitate DNArecombination. The mutations responsible for hereditary angioedemausually impair DNA transcription, but the disease has also beenreported in association with untranslated RNA and with defectsimpairing the secretion of mutant protein (5).
PATHOGENESIS
C1 inhibitor is centralto the regulation of the complement, coagulation, and contact(kinin-forming) systems. As a member of the family of the serineprotease inhibitors (serpin), C1 inhibitor acts as a "suicideprotein" by forming complexes with the target proteases. Itinhibits C1r and C1s in the complement system, HF (Hageman Factor)and kallikrein in the contact system, factor XI in the coagulationsystem, and plasmin in the fibrinolytic system. Patients withC1-inhibitor deficiency have low plasma levels of C4 and C2, thesubstrate of the C1r-C1s complex.
Acute attacks ofangioedema simulate the appearance of cleaved,high-molecular-weight kininogen, the substrate of kallikrein andbradykinin release.
Defective synthesis ofC1INH accounts for 90% of Type I cases. When assayed antigenically,C1INH level is less than 30% of normal. Landerman (6) and Donaldson(7) found abnormalities in the kallikrein cascade and in thecomplement system. Lepow, et al (8) purified C1INH.
CLINICALFEATURES
The characteristics ofthe disease make early diagnosis difficult. Cases are frequently(and erroneously) associated to allergy. Swelling is thought to becaused by the release of vasoactive peptides that have proveddifficult to identify. Histamine has no role in this type of edema,which probably is due to the generation of substances with kininactivity. Whether the substance is a complement-derived, kinin-likepeptide or bradykinin itself is unclear. Other vasoactivesubstances may also be involved (9). In 1965, Rosen, et al (10)described a small group of patients with C1INH function and normalor increased antigen levels. In our series, 5.68% (5 patients) ofour cases were of this type (type II).
A third group of patientswas described by Caldwell, et al (11) in 1975. These patients haveclinical manifestations of angioedema secondary to systemic diseasesuch as colon cancer, lymphoproliferative diseases, autoimmunediseases, anti-idiotype antibodies, and others. These clinicalforms of angioedema tend to appear in the adult age and areinfrequent in childhood. In our series, 3 patients (3.41%) belongedto this group, Type III (Figs. 1 to 3).
Figure1.--Relative percentages of symptoms during episodes.
Figure2.--Symptom location in children under 10 years.
Figure3.--Distribution of HA types.
IMMUNOLOGICALDIAGNOSIS
At the Argentine Allergyand Immunology Institute we have diagnosed 88 patients with HAsince 1978. In this population, we detected 19 previouslyasymptomatic patients under the age of 10 years when symptomsbegan, the youngest of them 4 months-old (later corroborated at theage of 18 months).
In the complement system,C1INH deficiency is characterized by low antigenic levels of C4component due to increased consumption of this protein (Fig. 4).Serum levels of C2 esterase also are low.
Figure4.--Adapted from Kaplan (13).
In the laboratorydiagnosis, antigenic concentrations of C4 in serum are the firstindicator of HA. Antigenic C4 values are 30% of normal value(normal 20-60 mg/dl) at any time. In Type I HA, antigenic C1INHvalues are about 30% of normal, frequently less than 10 mg/dl.Normal C1INH values are 17-31 mg/dl (by radial immune diffusion,RID). Functional C1INH is required to characterize this illness asType II. Using the Kent and Fife method for measuring functionalC1INH, values are lower than 80% (normal range:80-120%).
CH50 values are low atany time without treatment, about 100 ± 20 HU CH50 (2). Insecondary angioedema (Type III), C1q is always low, thusdifferentiating Type III from the other types of HA.
In Type I, C1q wasdecreased in 10% of our adult patients at the beginning of thestudy, indicating intensive complement activity (12).
In our population of HApatients, 56% had circulating immune complexes (CIC) as evaluatedby two different methods (C1q in solid phase and complementconsumption). We attribute this increase in immune complexes toconsumption of C4 and C2 by the activated complement system, thusimpeding the generation of C3 convertase and production of C3bfragment, the main component of plasmatic CIC clearance. On theother hand, C3 turnover involves the most active fraction of thecomplement system, so the C3 fraction remains within normal values,even during episodes. C4 is always low, even betweenepisodes.
HF activation determinesan active fraction, HFf, which activates C1r and consumes C1s, C4,and C2. C1 is decreased in 90% of our cases in Type I and II HA(Fig. 4).
COAGULATION ANDCOMPLEMENT IN HA
C1INH regulates not onlythe complement system, but also the contact and fibrinolyticsystems of coagulation, so these systems share links.
* C1INH is important forthe inactivation of Hfa (activated) and HFh (fragment of thecontact system. It inhibits approximately 90% of the protein andits fragment (14).
* C1INH is clearly animportant inhibitor in the control of the plasma kinin-formingsystem. In 1962, Landerman demonstrated that the plasma of patientswith HA was deficiency in kallikrein-inhibiting capacity comparedwith normal plasma (15).
* C1INH also regulatedplasmin, the fibrinolytic protein, and in 1952 the group of Lepowdemonstrated that this protein could reciprocally inactivate serumcomplement (16).
It is interesting to notethat strenuous exercise, anxiety, and trauma; the only demonstratedcauses of HA episodes, also enhance fibrinolysis.
Two different hypotheseshave been proposed to explain the pathogenesis of HA episodes. Thefirst hypothesis involves a C2 fragment: the authors suggest thatactivated C1 cleaves C4 and C2, and a fragment of C2 kinin formedduring cleavage could produce edema, thus causing HAepisodes.
The second hypothesisattributes episodes to bradykinin produced in this system.Recently, the group of Davis (17) published an interesting articlein which they suggest that bradykinin triggers HA. They studied afamily without HA who presented a dysfunctional C1INH; in thismutant, Ala 443 (P2) has been replaced by Val. The protein has lessinhibitory activity toward isolated C1r, C1s, and intact C1, butcan completely inhibit Hfa and Kallikrein.
Consequently, the normalinhibition of the contact system and abnormal inhibition of thecomplement system in members of a family without HA episodessuggest that episodes are triggered by bradykinin generated in thecontact system.
At present, mostresearchers believe that this is the most likely hypothesis. Inearlier studies (18) we found fibrin deposits in the skin biopsiesof asymptomatic patients with HA between episodes. Recently, Cugno,et al (19) demonstrated the active participation of thrombin in HAepisodes. This observation could be related with our findings,because thrombin, the enzyme responsible for fibrin formation,occurs during edema episodes.
In a group of symptomaticpatients, we studied parameters of the coagulation and complementsystems before and after treatment with danazole. We observed anincrease in the plasma concentrations of C1INH, C4, protein C (PC),plasminogen (plg), and HF coagulant activity (HFc) after drugtreatment. These observations confirmed published findings andmotivated us to begin a more detailed study of the links betweenthese two systems.
TREATMENT BETWEENEPISODES
The clinical use byGelfand (20) of danazole, an attenuated androgen, increased hepaticsynthesis of C1INH by the normal gene.
We prescribed doses of400 mg/day for 14 days ant then measured biochemical markers. SerumC1INH did not reach normal levels, but the patient remains free ofclinical symptoms. However, a marked increase to below-normalvalues was observed of serum C4 fraction levels, possibly due to adouble mechanism, a decrease in activation and an increase in liversynthesis.
At our institute, minimaleffective doses are evaluated as follows:
1) If the patient hadCIC, CIC should disappear from serum after 14 treatmentdays.
2) C4 fraction levelsincrease by 80% with respect to baseline value.
The resting period mustnot exceed 5 days. Danazole was found to be ineffective at doseslower than 200 mg/day in the early treatment period(21).
This drug is indicated inadult men or women with frequent, life-threatening symptoms. Commonadverse effects are weight gain, hirsutism in women, and impairedlibido in men. We observed microhematuria in two male patients andabnormal hepatogram in two women.
Epsilon aminocaproic acid(EACA) is another recommended drug. We prescribe doses of 1 g/dayto prevent episodes in adults, and half that dose in children asneeded. The mechanism of action is unknown. Adolescents, childrenwith relatively frequent episodes, or young women with mild edemaepisodes and no laryngeal or mouth edema are treated. Tachyphylaxisin frequent after a one-year treatment with 1 g/day.
TREATMENT OFEPISODES
We reserve theadministration of C1INH concentrates for rescue treatment. Weprescribe 1000 U to each family to keep at home for emergency usebecause the product is very expensive and difficult to obtain inArgentina.
The transfusion of freshplasma in acute episodes of laryngeal edema was beneficial in fourof our patients. However, its use is controversial because plasmamay add C1 esterase-activating factors and transmit HIVvirus.
For acute bowel episodeswe prescribe EACA, which is relatively effective in relievingsymptoms.
Of 3 patients withsecondary HA (type III), one was associated with systemic lupuserythematosus and two had no other primary diseasediagnosed.
One of these two patientsdied of tongue edema initiated by an episode. In this case, theandrogen previously used at doses of 800 mg/day did not improvesymptoms or immune system determinations. Fresh plasma transfusionswere not effective during acute episodes.
Although some minorprocedures may trigger episodes, many of our patients who haddental extractions before diagnosis did not have serious problems.However, we recommend caution in the case of dental treatment,insertion of nasogastric tubes, tonsil surgery, or otherinterventions on the mucosa because HF activation in situmay originate bradykinin release. In these cases we recommenddanazole 400 mg/day for 14 days before and 7 days after theintervention, or C1INH concentrates when the androgen is notindicated, especially in children.
CONCLUSIONS
1. C4, the first markerof the disease, should be evaluated in every patient with recurrentedema or bowel colic of no known cause at any age.
2. After C4, we assayantigenic C1INH, C1q, and functional C1INH if antigenic C1INH isnormal or high.
3. Atopy is associatedwith HA in 24% of adults and 14% of patients under 10 years ofage.
4. HA can skipgenerations.
5. Spontaneous appearanceof HA is caused by different genetic disorders. This situation isfrequent.
6. Family members must bestudied when HA is detected. It is important to detect asymptomaticchildren.
