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Introduction

Hereditary angioedema
Quincke first described and named angioneurotic edema (1), the striking influence of mental stress on the disorder led to the term neurotic which now is abandoned as the genetic cause is known. Nathaniel Hawthorne was apparently familiar with this disorder for in his 'House of the Seven Gables' (2), he describes the Pyncheon family with members who gurgled in the throat and chest when excited and who would sometimes die this way, ever since a curse to choke on blood had been placed on one of their ancestors. The following passages could indicate that Hawthorne recognised that a hereditary disease, not a curse, was responsible for the deaths: "This mode of death has been an idiosyncrasy with his family, for generations past" and "the curse,.. had become a part of the Pyncheon inheritance" (3).

Persons with hereditary angiodema are victims of recurrent bouts of edema which may occur in nearly every part of the body (Fig. 1 - 3). Attacks typically last for 2 to 5 days. The disease has been reviewed in several papers (4-11).

Skin

Fig. 1.Attack of HAE with moderate swelling of the right arm and hand. The picture may be used for educational purposes only.

Swellings most often involves the deep skin of extremities, genitals or face. In certain cases the swellings migrate around the body. Mottling, serpiginous or circular red rings may herald attacks. The rash bear some resemblance to urticaria, but do not itch (12). The swellings are non-pitting, non-pruritic and usually not painful. The edematous transformation of the face may occasionally be so severe as to frighten relatives.

Gastro-intestinal tract
The most incapacitating symptoms stem from the edematous expansion of the gut wall which can be seen on ultrasound or when these patients erroneously have undergone laparotomy (13-16). The most frequent morbid outcome of C1-INH associated angioedema could in fact be unnecessary abdominal surgery (17-19). The crampy abdominal pain and often profuse vomiting confine the patients to bed. The extravasation of fluid into the peritoneum manifest as ascites or, when entering the gut lumen, as watery diarrhea (8,20-25). HAE patients frequently suffer from ulcer or heartburn (14,26-28).

Airways
Nasal obstruction and sinusitis are experienced by some (14,29,30). Laryngeal edema may progress to complete airway obstruction (4,31,32). The incidence of sudden death due to suffocation has been reported as high as 54% in some affected kindred, while 20-30% are more often cited (4,8). Pleural effusions and pulmonary edema have been observed (11,31,33-36).

Fig. 2. Attack of HAE involving face and oral cavity. Girl from the county of Nordland . The picture may be used for educational purposes only.



Uro-gentital tract
Although infrequently reported, attacks of HAE may be accompanied by dysuria, hematuria, inability of passing urine and spasmodic pain in the urinary tract (6,37-39). Women with HAE frequently have polycystic ovaries in the presence of high beta-endorphin concentrations (40). Sexual intercourse can provoke edema of the genitals (33), a 15cm scrotal edema has been noticed (14) and vaginal delivery may precipitate attacks (41) or edema of the vaginal wall may lead to a difficult parturition (42).

Brain
Serious attacks of cerebral edema and circulatory disturbances are rare, but may cause transitory ischemic attacks and fatal cases are described (8,31,33,43-46).

Circulatory system
Dispersion of fluid into tissues during attacks is usually mild, but may occasionally bring about severe hemoconcentration. Fainting and symptoms of hypovolemia often succeed (15). Some patients reportedly suffered from hematocrit values of 75% (47).

Autoimmune diseases
Numerous case reports and a few larger investigations link hereditary angioedema with autoimmune diseases. Glomerulonephritis and lupus like disorders are most frequently reported, while Sjögren's syndrome, inflammatory bowel disease, thyroiditis, systemic lupus erythematosus, aortitis and rheumatoid arthritis are more rarely encountered (46,48-58).

C1-INH plays an important role in regulating nonspecific complement activation, but has only limited effect on immune complex-induced C1 activation or when C1 is activator-bound (59-61). An overabundance of spontaneous C1 autoactivation, due to low C1-INH levels, underlies the abnormal activation of complement via the classical pathway seen in HAE patients (62). It is assumed that this consumption may expose HAE patients to an increased risk of immune-complex disease, as seen in patients genetically deficient of C2 and C4 (11,63,64). Explanations of a decreased solubility of immune complexes are given (65), as the classical pathway of complement has a pivotal role in keeping antigen-antibody complexes small and soluble. The end result is the covalent binding of C3b to the antigen-antibody lattice, which not only keep these immune complexes soluble, but permits binding to complement receptor 1 (CR1) for removal from the circulation (66). Other studies did not show increased levels of circulating immune complexes and argue for other mechanisms (67). However, the largest clinical study on HAE ever published failed to demonstrate a significantly higher prevalence of biochemical markers of autoimmune disease in HAE (11).

Inciting events
Many individuals with HAE will respond to mental stress by having an attack, and this is allegedly why Quincke more than a 100 years ago designated the disease as angioneurotic (1). The intake of estrogen containing pills regularly worsen symptoms (68-71). Ear nose and throat surgery, particularly dental extractions, or infections often initiate local swellings and at times life-threatening obstructions of the upper airway (39,72-80). Sustained pressure from shoes, clothes or repetitive thumps often so mild as to be unnoted by unaffected persons, may also initiate attacks. The type of provocative events which cause attacks, however, is highly variable from patient to patient (81), and even within the same patient (6,11). Very often, there is no clue as to the cause of the attack.

Genetics
The disease is inherited as an autosomal dominant trait. The C1-INH gene is localised on chromosome 11 (82). Heterozygous patients have one normal and one mutated allele, homozygous patients have not been reported. Two types of HAE has been described, both types have reduced levels of functional C1-INH stemming from only one normal allele. In type I HAE the mutant allele produces no C1-INH protein or one that is not detected by conventional antigenic methods, but in type II, a dysfunctional C1-INH protein from the mutant allele can be detected antigenically. Newly, sensitive methods have detected minor amounts of a defective C1-INH protein from the sick allele also in some type I HAE patients, defying the conventional classification of C1 inhibitor deficiencies as type I or type II (83,84).

C1-INH values are generally lower than the 50% expected from a heterozygous condition, typically 10-30%. Explanations have been given of a negative feedback from the sick allele on the normal, thereby lowering the production (85). A more likely explanation is an increased consumption of C1-INH in HAE patients, caused by a continous activation of proteases. An original C1-INH content of 50% is probably too low to keep control of the cascades (86,87).

Pathophysiology
During attacks, endothelial cells in postcapillary venules contract which allow fluid and plasma proteins to leak between them (88). The mediators of these events are not fully determined. Bradykinin, liberated from high molecular kininogen by the unopposed enzymes kallikrein and factor XII is important, as C1-INH is the major inhibitor of these proteases (89-91). The theory of a kinin like molecule from C2 by plasmin is now attenuated (92,93). C4a probably plays a subordinate role (94).

Diagnosis
The disease has often been misinterpreted by clinicians (14,95-98). A 46 year old man underwent 3 laparotomies, an appendicectomy, a cholecystectomy, partial resection of the terminal ileum, a Noble's plication (to prevent intestinal adherences), and insertion of a Baker's tube (a long tube to prevent small bowel obstruction) and 15 years of treatment with steroids, before receiving the diagnose HAE. On two occasions a psychiatric opinion had been obtained and electroconvulsive treatment given (18).

Fig.3. Endoscopic photo of edematous gastric folds during attack of HAE, the first ever published. The diagnosis was not known at the time. Man from the county of Nordland. The picture may be used for educational purposes only.

Symptoms of recurrent swellings and crampy abdominal pain lasting for days rather than hours, with serum samples showing reduced C1-INH function or antigen, often below 20%, accompanied by low C4 values are hallmarks of hereditary angioedema. A suggestive family history obtained after thorough examinations on the characteristic symptoms with similar biochemical findings should follow in most cases. Conversely, a finding of C1-INH values compatible with HAE in only one single person, should raise suspicion of dealing with in vitro artefacts or acquired angioedema. In vitro artefacts can be due to cold promoted activation in test tubes, in which kallikrein, weakly inhibited by C1-INH at low temperatures, may cleave several plasma proteins including C1-INH (99-104). This will give false low functional C1-INH values. Acquired angioedema is not genetically transmitted, but rather caused by extensive complement activation as in B-cell lymphoma and some other conditions, in which both C1 and C1-INH are consumed. Auto-antibodies against C1-INH can also produce acquired angioedema, which clinically can be indistinguishable from HAE (105-122) .

Treatment
Tranexamic acid has some effect in alleviating symptoms of HAE (13,123-125), but danazol has proven more effective (126-134). By intermittent and low-dosage use in periods with frequent attacks, side effects of this attenuated androgen can be avoided or minimised. Androgens augments the production of C1-INH from the normal allele (135). Acute therapy should address an edematous airway, and intravenous infusion of at least 1000 Units of virus inactivated C1-INH concentrate is successful in stopping airway swelling, usually within ½ h (69,128,136). The use of antihistamines, corticosteroids and adrenaline during an attack is generally not helpful (8,14,31,137,138).

Next: Introduction: Plasma cascade systems with emphasis on the role of C1-inhibitor