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C1 INH deficiency:
Q1: Is always associated with peripheral angio-oedema and urticaria
C1 INH deficiency is not associated with urticaria but the angio-oedema may be preceded by a serpiginous erythematous rash which is non-pruritic. Peripheral angio-oedema is a well recognised presentation but mucosal angio-oedema can be life threatening and may involve the bowel.
Q2: Symptoms can be precipitated by the oral contraceptive pill
The oral contraceptive pill and menstrual cycle have been linked to exacerbations of the condition but the most commonly reported precipitating factors are trauma, dental extraction, and emotional stress.1
Q3: Is the most commonly described genetic defect of the complement system and is characterised by a reduction in complement proteins C3 and C4
It is the most commonly described genetic defect of the complement system2 in which C4 and C2 are reduced due to the unchecked activity of C1, but C3 is invariably normal. This is because C3 convertase is not generated due to C4b and C2b being rapidly inactivated in the plasma.
Q4: Is inherited in an autosomal recessive manner and usually presents in the first decade of life
C1 INH deficiency may be inherited in an autosomal dominant (chromosome 11, p11.2–q13 ), manner where it usually appears early in life, or acquired presenting in the fourth decade or later.3 Quantitative (85%) and qualitative (15%) deficiencies of C1 INH are responsible for the inherited variety2 while an increased catabolic rate and autoantibodies to C1 INH are responsible for the two acquired forms.4
Q5: Is primarily treated with fresh frozen plasma which has replaced steroids and antihistamines as the treatment of choice during acute episodes
C1 INH concentrate is preferred for the acute episode, because fresh frozen plasma contains C1 and C2 which may aggravate symptoms.
Q6: May be treated by antifibrinolytic drugs, particularly in the acquired variety or in those not responding to androgens
Prophylactic treatment is by substituted androgens (stanozolol) and antifibrinolytic drugs (tranexamic acid). Antifibrinolytics are the treatment of choice before puberty and in women trying to conceive.
Angio-oedema was originally documented by Milton in 1876,4 while Osler described hereditary angioneurotic oedema in 1888.5 Donaldson et al first recognised that a deficiency of C1 INH was the cause of hereditary angio-oedema in 1963.6 C1 INH is a 104 kDa protein and its deficiency is the most commonly described genetic defect of the complement system.2 It acts as a serine protease inhibitor upon the C1qrs enzyme complex of the classical complement pathway as well as those of the kallikrein and plasminogen pathways. It is believed that angio-oedema is a result of reduced C1 INH function through a reduced inhibition of kallikrein, complement system activation, and kinin generation.7
A common presentation of C1 INH deficiency is that of recurrent episodes of acute, colicky abdominal pain associated with vomiting. Reports exist of patients undergoing operative exploration in the mistaken belief that a surgical emergency underlies the abdominal pain.8 Findings at operation include a large amount of serous fluid and intestinal wall oedema, which can lead to intussusception and hypovolaemic shock. Our case was saved from laparotomies because the diagnosis of “abdominal migraine” had been made repeatedly. Non-mucosal angio-oedema is usually well demarcated, localised, and most commonly found affecting skin on the extremities. The mucous membranes of the mouth, pharynx, and larynx may be involved.
Trauma, dental extractions, and emotional stress are among the most common precipitating factors, while the menstrual cycle and oral contraceptive pill have also been linked to exacerbations of the condition.1
Initial investigations of suspected C1 INH deficiency should include measurement of the complement components C2, C3, C4, and C1 INH. Further immunological investigations may include assays for functional C1 INH, C1, and C1 autoantibodies. If acquired C1 INH is suspected serum electrophoresis may identify the monoclonal paraprotein of a B cell lymphoproliferative condition. Barium studies during abdominal pain may show a classical “stacked coin appearance”, but confirmation is achieved by quantitative and qualitative measurement of C1 INH.
Treatment of the acute episode is preferentially with C1 INH concentrate which should also be used prophylactically before surgery. The use of fresh frozen plasma is controversial because it contains C1 and C2, which may aggravate symptoms.
Prophylactic treatment is by substituted androgens (stanozolol) and antifibrinolytic drugs (tranexamic acid). Antifibrinolytics may be effective in the acquired variety, those not responding to androgens, and are indicated before puberty and in women trying to conceive. Treatment of associated conditions may lead to symptomatic improvement in acquired C1 INH deficiency.
Affected individuals should wear Medic Alert bracelets. Genetic counselling and screening should be offered to their families, even those apparently not affected, because the clinical course of the disease can be so varied.
The diagnosis of C1 INH deficiency is frequently missed, as happened in our patient over a period of 14 years. It should be considered in any case of recurrent abdominal pain for which no obvious cause can be found.
C1 esterase inhibitor deficiency:
Commonest complement deficiency
Significant morbidity and mortality
Easy and cheap to diagnose
Should be considered in any case of recurrent abdominal pain for which no obvious cause can be found