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• Does normal C4 exclude hereditary angioedema (HAE)?
  Robert J Lock
  Published on: 18 April 2016

• Published on: 18 April 2016

  Does normal C4 exclude hereditary angioedema (HAE)?

  • Robert J Lock, Principal Clinical Scientist
  • Other Contributors:
    • Mark M. Gompels and Paul F.Virgo

  Dear Editor

  We read with interest the case report from Karim and colleagues in the Journal.[1] This case raises an important issue.

  Our study [2] has been quoted as suggesting that we have described HAE with normal C4. We do not entirely accept this interpretation. Although there were HAE patients with normal C4 this was only achieved whilst on adequate treatment. All 20 HAE patients in whom we were able...

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  Dear Editor

  We read with interest the case report from Karim and colleagues in the Journal.[1] This case raises an important issue.

  Our study [2] has been quoted as suggesting that we have described HAE with normal C4. We do not entirely accept this interpretation. Although there were HAE patients with normal C4 this was only achieved whilst on adequate treatment. All 20 HAE patients in whom we were able to identify samples either pre-treatment or when off treatment had a low C4 (sensitivity 100%).

  This study prompted a review of 44 cases with a presumed diagnosis of HAE and we have shown that misdiagnosis is not uncommon.[3] Of relevance to the case of Karim and colleagues, two patient samples had apparently low immunochemical C1 inhibitor levels but this was shown to be a method- dependent phenomenon and levels were normal when rechecked at a second laboratory. A further confounding factor was that one laboratory was using an inappropriate reference range for C4, based on historical data. Recent UK National Quality Assessment Scheme returns have highlighted the importance of having current local reference ranges, as there are substantial differences between some user groups.

  Patients with normal C4 and putative HAE have been described previously. Frank and colleagues [4] describe 4 angioedema cases with normal C4 but it is unclear from the text whether this is at presentation or on treatment. Importantly they note that C4 is never normal during an attack. Sánchez Palacios and colleagues describe an unusual patient with chronic angioedema, low C1 inhibitor and normal C4 but the diagnosis is unclear[5]. On balance, HAE (Type I or Type II) seems unlikely. Our study [3] confirmed that ‘in unequivocal HAE, at presentation or when off treatment, C4 is invariably below 40% of the normal mean level’.

  The case of Karim and colleagues, describing angioedema with a normal C4, is interesting. In these circumstances there may be alternative causative mechanisms, other than HAE Type I or Type II, such as activation of the of the kallikrein-bradykinin pathway. Reporting of such cases is essential for further clarification. However, without further information (i.e. genetic and functional studies on the family) we cannot conclude that this represents a case of HAE Type I or Type II.

  Serum C4, as with any pathological investigation, must be interpreted in the clinical context of the patient. Serum C4, with a locally validated reference range, is a very reproducible and reliable screening test for HAE Type I and Type II.[2] However, in the face of a strong family history or clinical history it should not be the sole test. This does not invalidate the use of C4 as a screening test, especially in a condition with a low prior probability and demanding immunochemical and functional assays.

  References

  1. Karim, Y., Griffiths, H., Deacock, S. Normal complement C4 values do not exclude hereditary angioedema. J Clin Pathol 2004;57:213-4.

  2. Gompels, M. M., Lock, R. J., Morgan, J. E., Osborne, J., Brown, A., Virgo, P. F. A multi-centre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency. J Clin Pathol 2002;55:145-7.

  3. Gompels, M. M., Lock, R. J., Unsworth, D. J., Johnston, S. L., Archer, C. B., Davies, S. V. Misdiagnosis of hereditary angioedema (Type 1 and Type 2). Br J Dermatol 2003;148:719-23.

  4. Frank, M. M., Gelfand, J. A., Atkinson, J. P. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;84:580-93.

  5. Sánchez Palacios, A., Schamann Medina, F., García Marrero, J. A. Chronic angioedema. Three relevant cases. Allergol et Immunopathol 1998;26:195-8.

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  Conflict of Interest:
  None declared.

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