血管性水腫

血管神經性水腫（Angioedema）或血管性水腫是真皮、皮下組織、黏膜的局部腫脹。可發生於面部、舌頭、喉、腹部、四肢。常與蕁麻疹相關，蕁麻疹是皮膚的紅腫。約數分鐘至數小時內發病。

基本機制涉及組胺或緩激肽。與組胺相關的是由於對過敏原的過敏反應，如蚊蟲叮咬、食物或藥品。與緩激肽相關的是遺傳問題稱作獲得性C1酯酶抑制劑缺乏，藥物有血管緊張素轉換酶抑制劑, 或淋巴組織增生性疾病.

為保護呼吸道通暢，對呼吸道特別是喉部發作水腫，必要時應進行氣管插管或環甲膜切開術。組胺相關血管神經性水腫可抗組織胺藥：對症治療常採用抗組胺受體H1拮抗劑，對頑固的、應用抗組胺受體拮抗劑無效的患者，可合併應用抗組胺受體H2拮抗劑如西咪替丁（甲氰咪呱）或蘭替丁，有時可取得滿意效果。酮體芬亦可合併使用。擬交感神經藥物主要用於急性蕁麻疹和（或）神經性水腫，尤其是喉水腫患者，應用0.1%腎上腺素皮下注射，對嚴重急性過敏性反應可隔20~30分鐘注射。同時給予糖皮質類固醇激素靜脈滴注，氨茶鹼口服或靜脈注射。緩激肽相關的疾病可用C1酯酶抑制物, 艾卡拉肽, 艾替班特治療。新鮮冷凍血漿也可作為替代療法。美國每年約十萬人發生此病。

## 症狀

The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell over the period of minutes to hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy or painful. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Tracheal intubation is required in these situations to prevent respiratory arrest and risk of death.

Sometimes, the cause is recent exposure to an allergen (e.g. peanuts), but more often it is either idiopathic (unknown) or only weakly correlated to allergen exposure.

In hereditary angioedema, often no direct cause is identifiable, although mild trauma, including dental work and other stimuli, can cause attacks. There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash. These stomach attacks can last one to five days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an acute abdomen (e.g. perforated appendicitis) it is possible for undiagnosed HAE patients to undergo laparotomy (operations on the abdomen) or laparoscopy (keyhole surgery) that turns out to have been unnecessary.

HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12–36 hours and then subsides within 2–5 days.

## 診斷

The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor. HAE type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 levels and function.

The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of hereditary angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.

Angioedema is classified as either hereditary or acquired.

### 獲得性血管性水腫

Acquired angioedema (AAE) can be immunologic, nonimmunologic, or idiopathic. It is usually caused by allergy and occurs together with other allergic symptoms and urticaria. It can also occur as a side effect to certain medications, particularly ACE inhibitors. It is characterized by repetitive episodes of swelling, frequently of the face, lips, tongue, limbs, and genitals. Edema of the gastrointestinal mucosa typically leads to severe abdominal pain; in the upper respiratory tract, it can be life-threatening.

### 遺傳型血管性水腫

Hereditary angioedema (HAE) exists in three forms, all of which are caused by a genetic mutation inherited in an autosomal dominant form. They are distinguished by the underlying genetic abnormality. Types I and II are caused by mutations in the SERPING1 gene, which result in either diminished levels of the C1-inhibitor protein (type I HAE) or dysfunctional forms of the same protein (type II HAE). Type III HAE has been linked with mutations in the F12 gene, which encodes the coagulation protein factor XII. All forms of HAE lead to abnormal activation of the complement system, and all forms can cause swelling elsewhere in the body, such as the digestive tract. If HAE involves the larynx, it can cause life-threatening asphyxiation. The pathogenesis of this disorder is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells. The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema "attacks".

## 病理學

緩激肽在各種血管性水腫中扮演了關鍵角色。這種肽是強力血管舒張並增加血管通透，導致組織液快速累積。這在臉部特別顯著，因為臉部皮膚相對缺少結締組織支撐，容易形成水腫。多種細胞類型在刺激下會釋放緩激肽。不同的干涉緩激肽生產或降解的機制能導致血管性水腫。血管緊張素轉換酶抑制劑會阻斷血管緊張素轉化酶（ACE）的降解緩激肽作用，可能進而導致血管性水腫。遺傳性血管性水腫是導致緩激肽生成的補體系統持續活化，因為缺乏相應的抑制劑：C1酯酶（C1INH）。這種絲氨酸蛋白酶抑制劑能抑制C1r、C1s與C1q的關聯，阻止了C1複合體的生成，從而激活了其他的補體系統的蛋白。此外還抑制了相應的一些凝血蛋白，雖然對出血與血栓形成的干擾效果是有限的。

有三類遺傳性血管水腫：

- 第一類 - C1INH的低濃度 (85%)。
- 第二類 - C1INH濃度正常，但缺乏功能 (15%)。
- 第三類 - C1INH無異常，伴性遺傳主要影響女性；懷孕與使用甾體激素者會加重 (發生頻率不定) 與哈格曼因子基因變異有關。

血管性水腫也可能是生成了C1INH抗體，這是一種自體免疫性疾病。與淋巴瘤的發展有關。

食物消化吸收後可能帶來自己的血管擴張劑，如酒精飲料或桂皮，可加重病情。菠蘿蛋白酶與薑黃合用能減輕症狀。中藥分別稱兩種效果為「發貨」與抗炎消腫。

布洛芬或阿司匹林可能會加重病情。對乙醯氨基酚也能加重病情。

## 治療

### 過敏

在變應性血管性水腫中，避免過敏原和使用抗組胺藥可以預防發作。西替利嗪是血管性水腫常用的抗組胺藥。一些患者聲稱，每晚服用低劑量的西替利嗪可成功減輕發作的頻率和嚴重程度，然後在發作時使用更高的劑量。嚴重的血管性水腫病例可能需要對假定的過敏原脫敏，因為可能會導致死亡。慢性病例需要類固醇治療，這通常會導致良好的反應。如果過敏性發作正朝著氣道阻塞發展，腎上腺素可能會挽救生命。

### 藥物導致

ACE inhibitors can induce angioedema. ACE inhibitors block the enzyme ACE so it can no longer degrade bradykinin; thus, bradykinin accumulates and causes angioedema. This complication appears more common in African-Americans. In people with ACE inhibitor angioedema, the drug needs to be discontinued and an alternative treatment needs to be found, such as an angiotensin II receptor blocker (ARB) which has a similar mechanism but does not affect bradykinin. However, this is controversial, as small studies have shown some patients with ACE inhibitor angioedema can develop it with ARBs, as well.

### 遺傳性

In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine. Acute treatment consists of C1-INH (C1-esterase inhibitor) concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. The medications ecallantide and icatibant may be used to treat attacks. In 2017 these medications cost between 5,700 and 14,000 per dose in the United States, prices that tripled in two years.

Future attacks of hereditary angioedema can be prevented by the use of androgens such as danazol, oxandrolone or methyltestosterone. These agents increase the level of aminopeptidase P, an enzyme that inactivates kinins; kinins (especially bradykinin) are responsible for the manifestations of angioedema.

活性減弱的雄性激素如達那唑、司坦唑（康力龍）、羥甲烯龍（康復龍）等治療先天性C1INH缺陷，可糾正其生化缺損並有預防發作的效用，但不能用於小兒和孕婦。

### 獲得性

獲得性血管神經性水腫、HAE的I型與II型、以及非組胺血管神經性水腫性，抗纖維蛋白溶酶藥物如氨甲環酸或ε-氨基己酸有時可控制自然發作，也適用於小兒和孕婦。桂利嗪可用於抗C4活化，適用於有肝病不能使用雄性激素的患者。

## 歷史

1882年，首次臨床報告此病。雖然有些更早的臨床描述。

1888年，威廉·奧斯勒認為某些是由於遺傳導致的，稱「遺傳性血管神經性水腫」。

1963年，證實了C1酯酶抑制劑匱乏是病因。

## 流行病學

在美國，急診室年度就診患者中有80,000至112,000是血管神經性水腫，是過敏導致就醫中的首位。

## 參見

- 藥物性血管性水腫
- 格萊希症候群 (不明原因的血管性水腫伴高嗜酸性粒細胞計數)

## 外部連結

- Health/Conditions_and_Diseases/Skin_Disorders/Hereditary_Angioedema/

## 基本資料

- 日語原文：血管神經性水腫
- 異名：血管性水腫，Angiooedema, Quincke's edema, angioneurotic edema
- 醫學專科：免疫學
- 症狀：局部腫脹
- 藥物代謝：幾分鐘到幾小時
- 類型：組胺調節, 緩激肽調節
- 風險：家族史
- diagnosis：對症治療
- 鑑別診斷：全身型過敏性反應, 膿瘍, 接觸性皮炎
- 管理層：插管, 環甲狀軟骨切開術
- 藥物：組胺: 抗組織胺藥, 皮質類固醇, 腎上腺素、緩激肽: C1酯酶抑制物, 艾卡拉肽, 艾替班特, 新鮮冷凍血漿
- 頻率：~100,000每年(美國)