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Number 4'2004

HEREDITARY ANGIOEDEMA: OPTIMAL TREATMENT IMPROVES QUALITY OF LIFE AND MAY BE LIFE-SAVING

Sara Lear, Bridget Heelan, Hilary Longhurst

Abstract

Hereditary angioedema due to C1 inhibitor deficiency is a rare condition causing intermittent dermal and submucosal swelling. Attacks are precipitated by infection or trauma, or may occur spontaneously. Laryngeal oedema may mimic anaphylaxis and is a medical emergency. Intestinal oedema may mimic an acute surgical emergency. Symptoms do not respond to adrenaline, antihistamines or corticosteroids and if C1 inhibitor replacement is not available, intubation or tracheotomy may be lifesaving. Patients often remain undiagnosed and in the absence of appropriate treatment have 35% mortality from laryngeal obstruction. Unnecessary surgery is a common consequence of severe abdominal attacks.

Appropriate management can greatly reduce the incidence and severity of attacks.

HAE is an autosomal dominant disease characterised by episodic angioedema swelling of any part of the body. It results from reduced function of the C1 esterase inhibitor protein leading to uncontrolled activation of several protein cascades within the serum - most notably the classical complement and bradykinin pathways. Symptoms usually start under the age of twenty but patients can remain undiagnosed for decades, often misdiagnosed as allergic or idiopathic angioedema, or anaphylaxis. Testing of family members is therefore important as the severe attacks in undiagnosed patients contributes to the 35% mortality in this group. (1;2)

Genetics

C1 inhibitor (C1inh) is encoded on chromosome 11, it is an alpha 2-globulin and is produced mainly in hepatocytes although activated monocytes, megakaryocytes, endothelial cells and fibroblasts synthesize small amounts (3). There are three types of HAE which are phenotypically indistinguishable:

HAE Type 1 (85% of cases) There is a deficiency in the amount of C1 inhibitor protein produced due to a non- functioning gene. This mutation results from a variety of insertions/deletions of single/multiple nucleotides within the C1inh gene and has an autosomal dominant, Mendelian pattern of inheritance, though approximately 25% arise from spontaneous mutation (4-7)

HAE Type 2 (15% of cases) There is normal or increased amount of dysfunctional C1 inhibitor protein. This is usually caused by point mutations at the Arginine 444 site which codes for the "the reactive centre" - the active binding/cleaving site of the molecule. Since dysfunctional C1 inhibitor is not consumed, it has a longer half life, leading to a higher serum concentration.

HAE, Type 3 (unknown prevalence) has recently been described where the plasma concentrations of C1 inhibitor are normal; the mechanism is unknown but does not appear to be related to the C1 inhibitor protein .(8) This type occurs only in females and pedigrees suggest an X linked dominant mode of inheritance. This type is not discussed further here.

Acquired angioedema (AAE) due to C1 inhibitor deficiency occurs in older people and is often associated with lymphoproliferative disorders, autoantibodies to C1 inhibitor or chronic infection.(9)

Pathophysiology

The main functions of C1 esterase inhibitor are

  • to prevent spontaneous activation of the classical complement cascade,
  • to inhibit coagulation factors XIa and XIIa regulating activation of the clotting cascade.
  • to inhibit of conversion of plasminogen to plasmin in fibrinolysis.
  • to inhibit activated kallikrein in the kallikrein -bradykinin pathway. (See figure 1)

Several end products of these cascades are vasoactive peptides, such as bradykinin or complement fragments, which induce increased local capillary permeability with fluid extravasation and , smooth muscle contraction in the gut /hollow viscerae. Local lack of C1 inhibitor causes lack of regulation and overproduction of these peptides, resulting in localised swelling. (1;10-12)

Diagnosis

The diagnosis should be considered in any patient presenting with recurrent angioedema or recurrent abdominal pain, in association with low C4 in serum samples. A normal C4 conveys a negative predictive value of 96% and usually excludes the need for further investigation. In type 1 HAE, further analysis will demonstrate low levels of C1 inhibitor, typically less than 30% of normal. In cases where C1 inhibitor levels are normal or high, C1 inhibitor function should be performed to identify type 2 HAE(13).

If acquired angioedema is suspected, investigations to identify possible underlying lymphoproliferative disease, SLE, hepatitis and other infections should be routine(14). C1q levels are low in acquired angioedema, but normal in hereditary angiodema.

Clinically

There is typically localised non pitting oedema which is non-pruritic and occurs particularly in the extremities, mucocutaneous surfaces and the viscera. If the upper respiratory tract is affected this tends to occur superior to the larynx with swelling of the lips, tongue and pharynx. This may be misdiagnosed as anaphylaxis or idiopathic angioedema. Oedema of the abdominal viscera is common resulting in severe muscle cramps, nausea, vomiting and diarrhoea. This often mimics an acute abdomen or obstruction: endoscopic and ultrasound examination are not usually indicated, but if performed show diffuse visceral swelling and ascites. Urticaria is not a feature of hereditary angioedema but some patients describe a prodromal erythema multiforme-like rash.(3-5;15)

Attacks vary in frequency and distribution both within a single individual, a family group and the HAE population. In contrast to anaphylaxis, symptoms commonly develop over several hours, are maximal for 12-36 hours before subsiding over 1-3 days. Frequency can vary from weekly to yearly attacks. Of importance, life threatening episodes can occur in patients with previously mild disease and can occasionally progress more quickly than usual (16;17)

Patients will present in one of three ways; as a severe life threatening event responding poorly to routine treatment of anaphylaxis: as a family member of an identified sufferer: or having spent many years with attacks treated as allergy or as psychosomatic illness. (See case history)

Exacerbating factors

Any factor likely to activate the classical complement pathway, the kallikrein-kinin system or the clotting cascade will lead to a higher requirement for C1 inhibitor and is a potential trigger for an attack. Trauma, surgical procedures and dental extraction are all well recognised precipitants(18;19) Angiotensin converting enzyme (ACE) inhibitors, oestrogen-containing oral contraceptives or hormone replacement therapy will also initiate attacks and should be avoided(20). Many patients identify other more diffuse triggers such as stress, or infection. Chronic infections, which may not be clinically evident, are associated with worse HAE symptoms and efforts should be made to diagnose and eradicate chronic infection such as H. pylori(21).

Long Term Prophylaxis

Long term prophylaxis is necessary in-patients with life threatening episodes or in those whose symptoms are recurrent and severe enough to disrupt quality of life. Antifibrinolytics (tranexamic acid, aminocaproic acid) may be safer in long-term use than androgens (danazol, stanozolol or in adult males, methyl testosterone) but are less effective.(22-25) In rare cases, where oral medication is ineffective or contraindicated, C1 inhibitor concentrate has been used successfully for long term replacement. Doses and contraindications are shown in Table 1.

Short term prophylaxis

Where there is a predictable trigger for an attack of angioedema, such as surgery or dental extraction, prophylaxis may be helpful. The need for prophylaxis should be considered on an individual basis, taking into account the severity of previous attacks and the nature of the procedure. All patients should be warned of the increased risk of an attack in the 36 hours following surgical or dental procedures, even if prophylaxis has been given. C1 esterase inhibitor, FFP, antifibrinolytics and attenuated androgens have each been used for prophylaxis. Therapy of choice is C1 esterase inhibitor given immediately prior to treatment. For more minor procedures, or where C1inhibitor is unavailable, higher doses of androgens, for example; danazol 600mg daily for 5 days before and after the procedure, or tranexamic acid are alternatives.(26)

Management of acute attacks

C1 inhibitor concentrate is the treatment of choice for all laryngeal and severe abdominal attacks. Patients should experience symptomatic improvement within 0.5-6 hours, although where treatment is delayed, or if the patient has acquired angioedema, higher doses may be required.(6;7;27) Peripheral attacks do not normally require treatment.

C1 inhibitor concentrate is not routinely available in Russia. Although plasma is effective, repeated transfusions are likely to be required and the risks, particularly of viral transmission, may outweigh benefits(28). Tranexamic acid orally or intravenously may shorten the attack, particularly if given early. High dose danazol may abort a developing attack, but its slow onset of action (over several days) limits its use in established attacks. It is most likely to be effective where prodromal features are present so that the patient can take it as soon as they are aware of an oncoming attack. The kallikrein inhibitor, aprotinin, is effective in acute HAE. However, anaphylactic reactions are common if repeated doses are given, limiting its use (Bork K, Personal communication).

Where neither C1inhibitor nor screened plasma is available, symptomatic treatment should be given: pain killers and fluid replacement for abdominal pain; for laryngeal involvement, intubation or tracheotomy is sometimes necessary to prevent asphyxiation. Intubation may be technically difficult and ideally should be performed by an experienced anaesthetist, with facilities for emergency tracheotomy available.

Conclusion

HAE due to C1 inhibitor deficiency is associated with significant morbidity and mortality. Accurate diagnosis, avoidance of precipitating factors, treatment of chronic infections and where necessary prophylaxis with attenuated androgens or tranexamic acid result in major improvement in prognosis and quality of life. C1 inhibitor is the treatment of choice for acute attacks but is not widely available in Russia. For this reason, optimising long-term prophylaxis and instituting short term prophylaxis to cover high-risk procedures is essential.


Figure 1. Sites of action of C1 inhibitor

Case History

A 76 year old man was referred to our clinic following the diagnosis of hereditary angioedema in his niece. His symptoms started in 1943 when he was 21 years old: he experienced intermittent swelling in his hands, face and genitals, and episodes of abdominal pain with associated vomiting. Attacks lasted 3-4 days and would occur up to 6 times a year. He had been advised in the 1950s that he was "allergic to a number of inhaled allergens" and was given antihistamine treatment which was ineffective. His family history was typical with his mother, brother and niece describing similar symptoms. Apart from symptoms compatible with mild prostatism he was other wise fit and healthy, with no abnormality on examination. His C4 was 0.09g/L (normal range 0.14-0.54) and C1inhibitor level was 56mg/l (normal range 150-350) confirming a diagnosis of C1inhibitor deficiency.

We decided to avoid danazol because of his prostatism He was commenced on tranexamic acid. His follow up appointments show a decrease in the number of episodes by approximately half, with improvement in quality of life, His dose of tranexamic acid was reduced and his symptoms were satisfactorily controlled on 500mg b.d. He has had no attacks severe enough to require C1 inhibitor infusion.

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