Our study collected the data from 103 type 1 HAE patients to analyze the natural course of HAE and explore possible risk factors. Two hundred and thirty-three family members with HAE of these 103 participants were included for the death statistics.
Patients with type 2 HAE were not included in this survey. Previous studies[6][14] have shown the lower percentage (< 5%) of type 2 HAE patients in China than expected (approximately 15–20%). The number of the type 2 case is relatively small, which is not sufficient to explore the difference between type 1 and type 2 in the natural course. The exclusion of type 2 patients ensured the homogeneity of the study subjects to some extent.
Our results show that under therapy-free conditions, the disease may firstly worsen as the age increased and showed a notable sign of deterioration especially during the age stage of 20 to 29. Then the symptoms were gradually relieved but maintained relatively severe until fifty years old. Patients may die of asphyxia due to the abrupt laryngeal edema with the median age of 46 (IQR, 35–53) years old. Consequently, although many patients in China are unwilling to take danazol due to side effects or unavailability, it is still recommended to conduct long-term prophylaxis and symptomatic treatment, especially for young and middle-aged patients.
The disease natural progression may provide some new insight to its pathogenesis. C1-INH-HAE results from the uncontrolled release of bradykinin from high molecular weight kininogen (HMWK) due to the deficiency of functional C1-INH. Previous studies have observed the level of kininogen increased with age in rat serum[15–18]. However, aging leads to weaker responsiveness to kinins[8] which is believed to be realized by the decreased density of the bradykinin receptors, lessening the vasoactive effects of bradykinin on the heart and vasculature[19–21]. And interestingly, vasodilation induced by bradykinin can be transformed into vasoconstriction under the conditions of vascular disorder or inflammation which is increased by aging and hypertension, a common chronic disease in older patients [22]. These findings may explain why the edema attacks caused by bradykinin turned to alleviate along with aging.
Our survey shows that nearly half of the patients had their first HAE attack during puberty and one third during their twenties. High levels of sex hormones may be one of the reasons why HAE deteriorates in youth. It is known that HAE is influenced by the fluctuation of estrogen[24–25]. Combined (estrogen and progestogen) oral contraceptives also has been found to worsen HAE for 80% of female patients[25]. Previous studies at molecular levels have confirmed that estrogen can increase the generation of kallikrein and bradykinin[26–27]and plays a role in the regulation of B2 receptor gene expression[28]. In a 2006 survey[23], more than 12 attacks of HAE occurred per year in 71 of 117 women (60.7%) and 34 of 78 men (43.6%), and the difference was significant (P < 0.020). In our study, both the median severity score and median edema resolution time of female patients were higher than those of male patients, but the difference was still not significant enough, with a P value of 0.067 and 0.179, respectively. Maybe the sample size needs to be expanded further.
Seven drinkers in our survey reported that alcohol could trigger an attack of HAE, and similar result was also reported before[31]. Alcohol is known to potentiate the action of bradykinin[32]. However, no significant difference was observed between the drinkers and non-drinkers. And interestingly, the median severity score and edema resolution time were lower in drinkers, which seem contrary to the previous description. Endothelial function and low-grade vascular inflammation are associated with dietary intake including alcohol[33]. Red wine consumption has been reported to cause less endothelial dysfunction and reduce inflammation in vasculature[34] while other studies found that heavy or even light alcohol consumption were associated with impaired endothelial function[35–36]. The relationship between the alcohol and endothelia is complicated, which may involve the type and amount of alcohol consumed, the age and race of the drinker, and many other factors. And how the endothelial dysfunction or inflammation affects the vascular permeability is also worth much more research.
We did not find other relative risk factors that may affect HAE natural progression, including smoking, though active and passive smoking has been found to blunt endothelium-dependent vasodilatations[37]. It may be due in part to the imperfect methods of scoring HAE severity. The disease severity is difficult to classify mainly for the changeability of symptoms, interference of subjective perception and no validated biomarkers[38]. And every HAE patient is at a risk for unpredicted laryngeal edema and death by asphyxiation, regardless of past symptoms, making the severity assessment more difficult. Based on the above reasons, we scored the severity according to edema frequency and locations to reduce the interference caused by changes over time or personal perceptions. But the scoring system is still not sufficient in its current form, and more researches are needed for the development of validated tools.