Q:

9/20/2013
Have a patient with abnormal CI Esterase levels. Started treatment with Danazol. Levels came back to WNL & patient had no signs/symptoms. Due to elevated LFT's, the patient came off Danazol. The patient now has increased signs & symptoms of HAE (limbs, gut & face involved). It has been 3 months since stopping Danazol & the patient has NORMAL C1 Esterase levels...What could be the reasoning? Could the patient have been mis-diagnosed or did he truly have a C1 Esterase inhibitor disease? Any input would be greatly appreciated!

A:

Thank you for the follow-up information regarding your patient who has been experiencing angioedema. The information was as follows:

Date of test:
10/20/11 C3 Complement = 124 Comp C1 Est Inhi= 10

C4 Complement=27.6 (14-40 mg/dL) C1 Est Inhib Fun= 55

11/23/11 C1Q = < 1.2 (12-22 mg/dL)

1/25/12 C3 Complement=107 C1 Est Inhib Fun= 80

C4 Complement=24.5

7/9/12 C3 Complement=104 Comp C1 Est Inhi= 12 Tryptase 1.40

C4 Complement=23.0 C1 Est Inhb Fun= 70

10/22/12 C1 Ester Inh Qnt-Mayo=>90 C1 Ester Inh Ag-Mayo= 28 (19-37 mg/dL)

9/6/13 C1 Ester Inh Qnt-Mayo = >90

>67% normal (normal)

41-67% normal (equivocal)

<41% normal (abnormal)

Also, just some added info: patient is a 50 year old male & since his LFT’s were abnormal with the Danazol, we will start him on Cinryze this week.

Unfortunately, I cannot give you a definitive answer for the question regarding whether or not your patient has C1 esterase inhibitor deficiency, but hopefully I can give you some insight in this regard, and suggest some things to pursue.

It is clear that treatment with Danazol can increase levels of C1 inhibitor and C4. However, I could find no study on the duration of this effect after cessation of treatment. My opinion, and I assume it was yours as well, is that three months would be too long for this effect to remain, but I cannot be sure of this because I found no data in the literature looking at this issue.

Thus, we have the following options to explain this variation:

1. The patient does not have C1 inhibitor deficiency.

2. C1 inhibitor deficiency was present, but the effect of the Danazol remained on C1 inhibitor levels after cessation.

3. The patient has C1 inhibitor deficiency, but the C1 inhibitor levels fluctuate for other reasons.

As noted, there is no definitive answer to your question, but it is important to try and pursue this issue. The main reason for this is a finding which you did not mention in your original inquiry, namely that your patient has a markedly low C1q. This was determined on 11/23/11 (three days after the original complement studies). A markedly abnormal C1q is not consistent with the hereditary form of angioedema (see abstracts copied below), but is found in acquired angioedema which can be associated with autoimmune diseases, an autoantibody against C1q, or neoplasms, especially those of the lymphoproliferative system. In addition, C1q levels, as can C1 inhibitor levels, vary with the status of the primary disease. So, I believe it would be important for you to investigate the possibility that your patient has acquired C1 inhibitor deficiency syndrome associated with one of the above conditions. Although it would not affect treatment by the administration of C1 inhibitor, it is known that the angioedema can remit with successful treatment of the primary disorder, if one does exist.

Thus, the fact that you started him on C1 inhibitor is good, but as a next step, I suggest that you investigate the possibility that your patient has the acquired form of C1 inhibitor deficiency.

I might also mention parenthetically that your patient has never exhibited a low C4 level. This of course does not rule out acquired or hereditary C1 inhibitor deficiency syndrome, but C4 levels are low in the vast majority of cases, especially during an episode. Thus I would also suggest that if an episode does occur, you obtain a repeat C4 during the event.

Thank you again for your inquiry.

Ann Allergy. 1990 Apr;64(4):388-92.
Hereditary angioedema: therapeutic effect of danazol on C4 and C1 esterase inhibitors.
Fabiani JE, Paulin P, Simkin G, Leoni J, Palombarani S, Squiquera L.
Source
Institute for Allergy and Immunology, Buenos Aires, Argentina.
Abstract
Hereditary angioedema (HAE) is an inherited deficiency of C1 esterase inhibitor (C1 inh). The two types of genetic C1 inh deficiency are type I, which is quantitative, and type II, which is functional. For the purpose of the present study, four HAE patients were selected. None of them had received any androgenic therapy. The group included three type I and one type II cases. All patients that entered the protocol received danazol, 400 mg/day for 14 days. The complement system was evaluated by monitoring C4, hemolytic complement 50% (CH50), circulating immune complexes (CIC), and antigenic and functional C1 inh during the study. The level of complement factors at the beginning and at the end of this period demonstrated a statistically significant increase in C4 and CH50 and the disappearance of CIC, while C1 inh remained unmodified. These results suggest that the therapeutic effect of danazol may have two mechanisms of action: (1) promotion of C4 synthesis by anabolic effect resulting in an improvement of the complement system with the disappearance of CIC and (2) a minor increase in C1 inh level primarily due to the lack of its consumption.

Am J Med. 1993 Aug;95(2):169-75.
Autoimmune C1 inhibitor deficiency: report of eight patients.
Cicardi M, Bisiani G, Cugno M, Späth P, Agostoni A.
Source
Clinica Medica III, Università di Milano, Italy.
Abstract
Purpose: In this study, we investigated the clinical and biochemical features and the responses to treatment of eight patients with auto-antibody-mediated C1 inhibitor (C1-INH) deficiency and symptoms of angioedema.
Patients and Methods: In addition to the 8 patients with acquired angioedema (AAE), we also studied 36 subjects with hereditary angioedema (HAE), 15 of them treated with C1-INH plasma concentrate, and 26 patients with different autoantibodies in their plasma (10 with systemic lupus erythematosus, 6 with lupus-like anticoagulant, and 10 with chronic liver disease). Functional C1-INH was measured with the reagent kit of Immuno (Vienna, Austria); C1-INH, C4, and C1q antigen were determined by radial immunodiffusion; and autoantibodies to C1-INH were detected by an enzyme-linked immunosorbent assay method.
Results: Four patients with AAE had no other diseases, one had breast cancer, one liver hydatidosis, one Waldenström's disease, and one a benign M component. Functional C1-INH levels were below 30% of normal, and C1q plasma levels were low in seven patients but normal in one. Autoantibodies to C1-INH were detectable in all eight AAE patients but in none of the others. Prophylactic treatment with attenuated androgens was successful in one of four patients, and with antifibrinolytic agents (tranexamic acid) in six of seven patients. Laryngeal attacks in five patients were treated with C1-INH plasma concentrate; two patients had marked clinical and biochemical responses. In three, the symptoms resolved only with high doses, and the biochemical parameters did not significantly increase.
Conclusions: Our results suggest that patients with autoimmune AAE are clinically and biochemically heterogeneous. They have different responses to treatment that seem to be related to variable C1-INH consumption.

Przegl Lek. 2002;59(6):438-41.
[C1 inhibitor deficiency. Heredity and acquired forms. Symptoms, diagnostic and therapeutic problems].
[Article in Polish]
Obtułowicz K, Kapusta M, Obtułowicz A, Mazurkiewicz A.
Source
Katedra Medycyny Pracy i Chorób Srodowiskowych Zakład Alergologii Przemysłowej Collegium Medicum, Uniwersytet Jagielloński, Kraków.
Abstract
C1 inhibitor deficiency can be hereditary (Type I and II) or acquired (Type I and II). Clinically it is manifested by recurrent attacks of angioedema which may involve skin, airways and digestive tract. The acquired form of C1 inhibitor deficiency is associated with lymphoproliferative or connective tissue disorders as well as with autoimmunization. Clinical symptoms are similar in all forms of C1 inhibitor deficiencies and they are connected with low serum level of C4 as well as with decreased activity of C1 inhibitor. In acquired angioedema additionally they are also decreased C1 and C1q and in type II C3 serum concentration is diminished. The drugs of choice are anabolics (danazol, stanazolol). Antifibrinolitic drugs are also used, especially in acquired forms of C1 inhibitor deficiency. The infusion of C1 inhibitor concentrate is used in acute emergency treatment.

Ann Intern Med. 2000 Jan 18;132(2):144-50.
Acquired C1 esterase inhibitor deficiency.
Markovic SN, Inwards DJ, Frigas EA, Phyliky RP.
Source
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55901, USA.
Abstract
Acquired C1 esterase inhibitor deficiency is a rare condition associated with autoimmune or low-grade lymphoproliferative disorders. Adults or elderly patients are most commonly affected. The diagnosis is suspected when patients present with recurrent angioedema and low serum levels of C4 with normal levels of C3. Low levels of C1q and low C1 esterase inhibitor activity confirm the diagnosis. In this paper, we summarize experience with 22 cases of acquired C1 esterase inhibitor deficiency in the context of a review of the published literature on diagnosis and treatment of this condition.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology