Review

. 2025 Mar 7;68(1):24.

doi: 10.1007/s12016-025-09027-4.

Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment

Bruce L Zuraw^#^{1

2}, Konrad Bork^#³, Laurence Bouillet^{4

5}, Sandra C Christiansen⁶, Henriette Farkas⁷, Anastasios E Germenis⁸, Anete S Grumach⁹, Allen Kaplan¹⁰, Alberto López-Lera¹¹, Markus Magerl^{12

13}, Marc A Riedl⁶, Adil Adatia¹⁴, Aleena Banerji¹⁵, Stephen Betschel¹⁶, Isabelle Boccon-Gibod⁴, Maria Bova¹⁷, Henrik Balle Boysen^{18

19}, Teresa Caballero^{11

20}, Mauro Cancian²¹, Anthony J Castaldo^{18

19}, Danny M Cohn²², Deborah Corcoran^{18

19}, Christian Drouet²³, Atsushi Fukunaga²⁴, Michihiro Hide^{25

26}, Constance H Katelaris²⁷, Philip H Li²⁸, Hilary Longhurst²⁹, Jonny Peter^{30

31}, Fotis Psarros³², Avner Reshef³³, Bruce Ritchie³⁴, Christine N Selva¹⁹, Andrea Zanichelli^{35

36}, Marcus Maurer^#^{12

13}

Affiliations

¹ Department of Medicine, Division of Allergy & Immunology, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA, 92093, USA. bzuraw@health.ucsd.edu.
² Medicine Service, San Diego VA Healthcare, San Diego, USA. bzuraw@health.ucsd.edu.
³ Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
⁴ University Grenoble Alpes, T-RAIG Unit, CNRS, UMR 5525, TIMC, Grenoble, France.
⁵ French National Reference Center for Angioedema (CREAK), Internal Medicine Department, Grenoble University Hospital, Grenoble, France.
⁶ Department of Medicine, Division of Allergy & Immunology, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA, 92093, USA.
⁷ Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
⁸ Department of Immunology & Histocompatibility, School of Medicine, University of Thessaly, Larissa, Greece.
⁹ Angioedema Center of Reference and Excellence (ACARE), Centro Universitario Faculdade de Medicina ABC (CEUFMABC), São Paulo, Brazil.
¹⁰ Medical University of South Carolina, Charleston, SC, USA.
¹¹ Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754), Madrid, Spain.
¹² Angioedema Center of Reference and Excellence (ACARE), Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹³ Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
¹⁴ Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹⁵ Department of Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Division of Clinical Immunology and Allergy, University of Toronto, Toronto, ON, Canada.
¹⁷ Division of Internal Medicine 2, Department of Medicine and Medical Specialties, A. Cardarelli Hospital, Naples, Italy.
¹⁸ HAE International (HAEi), Fairfax, VA, USA.
¹⁹ US Hereditary Angioedema Association (HAEA), Fairfax, VA, USA.
²⁰ Department of Allergy, La Paz University Hospital, Madrid, Spain.
²¹ Department of Systems Medicine, University of Padua, Padua, Italy.
²² Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
²³ Institut Cochin, Université Paris Cité, INSERM U1016, Paris, France.
²⁴ Department of Dermatology, Division of Medicine for Function and Morphology of Sensory Organs, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City, Osaka, Japan.
²⁵ Department of Dermatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
²⁶ Department of Dermatology, Hiroshima University, Hiroshima, Japan.
²⁷ Immunology & Allergy Unit, Dept of Medicine, Campbelltown Hospital and Western Sydney University, Sydney, Australia.
²⁸ Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
²⁹ Department of Medicine, University of Auckland and Department of Immunology, Auckland City Hospital, Auckland, New Zealand.
³⁰ Division of Allergy and Clinical Immunology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
³¹ Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa.
³² Department of Allergy, Athens Naval Hospital, Athens, Greece.
³³ Angioedema Research Unit, Barzilai University Medical Center, Ashkelon, Israel.
³⁴ Division of Hematology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
³⁵ Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
³⁶ Dipartimento Di Scienze Biomediche Per La Salute, University of Milan, Milan, Italy.

^# Contributed equally.

PMID: 40053270
PMCID: PMC11889046
DOI: 10.1007/s12016-025-09027-4

Review

Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment

Bruce L Zuraw et al. Clin Rev Allergy Immunol. 2025.

. 2025 Mar 7;68(1):24.

doi: 10.1007/s12016-025-09027-4.

Authors

Affiliations

¹ Department of Medicine, Division of Allergy & Immunology, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA, 92093, USA. bzuraw@health.ucsd.edu.
² Medicine Service, San Diego VA Healthcare, San Diego, USA. bzuraw@health.ucsd.edu.
³ Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
⁴ University Grenoble Alpes, T-RAIG Unit, CNRS, UMR 5525, TIMC, Grenoble, France.
⁵ French National Reference Center for Angioedema (CREAK), Internal Medicine Department, Grenoble University Hospital, Grenoble, France.
⁶ Department of Medicine, Division of Allergy & Immunology, University of California San Diego, 9500 Gilman Drive, Mail Code 0732, La Jolla, CA, 92093, USA.
⁷ Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
⁸ Department of Immunology & Histocompatibility, School of Medicine, University of Thessaly, Larissa, Greece.
⁹ Angioedema Center of Reference and Excellence (ACARE), Centro Universitario Faculdade de Medicina ABC (CEUFMABC), São Paulo, Brazil.
¹⁰ Medical University of South Carolina, Charleston, SC, USA.
¹¹ Hospital La Paz Institute for Health Research (IdiPAZ), CIBERER (U754), Madrid, Spain.
¹² Angioedema Center of Reference and Excellence (ACARE), Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.
¹³ Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
¹⁴ Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹⁵ Department of Medicine, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA.
¹⁶ Division of Clinical Immunology and Allergy, University of Toronto, Toronto, ON, Canada.
¹⁷ Division of Internal Medicine 2, Department of Medicine and Medical Specialties, A. Cardarelli Hospital, Naples, Italy.
¹⁸ HAE International (HAEi), Fairfax, VA, USA.
¹⁹ US Hereditary Angioedema Association (HAEA), Fairfax, VA, USA.
²⁰ Department of Allergy, La Paz University Hospital, Madrid, Spain.
²¹ Department of Systems Medicine, University of Padua, Padua, Italy.
²² Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
²³ Institut Cochin, Université Paris Cité, INSERM U1016, Paris, France.
²⁴ Department of Dermatology, Division of Medicine for Function and Morphology of Sensory Organs, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki-City, Osaka, Japan.
²⁵ Department of Dermatology, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan.
²⁶ Department of Dermatology, Hiroshima University, Hiroshima, Japan.
²⁷ Immunology & Allergy Unit, Dept of Medicine, Campbelltown Hospital and Western Sydney University, Sydney, Australia.
²⁸ Division of Rheumatology and Clinical Immunology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong.
²⁹ Department of Medicine, University of Auckland and Department of Immunology, Auckland City Hospital, Auckland, New Zealand.
³⁰ Division of Allergy and Clinical Immunology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
³¹ Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa.
³² Department of Allergy, Athens Naval Hospital, Athens, Greece.
³³ Angioedema Research Unit, Barzilai University Medical Center, Ashkelon, Israel.
³⁴ Division of Hematology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
³⁵ Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
³⁶ Dipartimento Di Scienze Biomediche Per La Salute, University of Milan, Milan, Italy.

^# Contributed equally.

PMID: 40053270
PMCID: PMC11889046
DOI: 10.1007/s12016-025-09027-4

Abstract

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

Keywords: Bradykinin; Diagnosis; HAE; HAE-C1INH; HAE-nC1INH; Pathophysiology; Treatment.

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Conflict of interest statement

Declarations. Ethics Approval: Not applicable for this literature review. Competing Interests: B.L.Z has served as a consultant for CSL Behring, KalVista, and BioCryst, on the DMSB for CSL Behring and BioMarin, and has had a laboratory service agreement with Ionis. K.B. reports no conflicts in relation to this manuscript. L.B. has consulted/served as speaker for, engaged in research and educational projects with or accepted travel grants from the following companies: BioCryst, CSL Behring, Takeda, Novartis, GSK, Blueprint, Kalvista, Pharvaris. S.C.C. has served on medical advisory boards for BioCryst, KalVista, and CSL Behring. She is a member of the Medical Advisory Board of the US HAEA. H.F. has received speaker fee and travel grants from CSL Behring, Pharming, Takeda, KalVista, and Pharvaris and served as an advisor/consultant for these companies and for Astria, BioCryst, Intellia, Ionis, and ONO Pharmaceutical. A.E.G. reports no conflicts in relation to this manuscript. A.S.G. receives a productivity grant from National Council of Research (CNPq) and a grant from researcher initiative from Shire/Takeda. A.S.G. reports speaking and/or consultancy fees from Catalyst, CSL Behring, Exeltis, KalVista, Multicare, Pharvaris, Pint-pharma, and Takeda. A.K. reports no conflicts in relation to this manuscript. A.L.L. reports conference travel support and speaking fees from Takeda and CSL Behring. M.Ml. reports honoraria or consultation fees from Astria, BioCryst, CSL Behring, Intellia, KalVista, Pharvaris, Shire/Takeda. M.A.R. has served as a research investigator for BioCryst, BioMarin, CSL Behring, Ionis, KalVista, Pharvaris, Takeda and a consultant for Astria, BioCryst, BioMarin, Celldex, CSL Behring, Cycle Pharma, Grifols, Intellia, Ionis, KalVista, Pfizer, Pharming, Pharvaris, Sanofi-Regeneron, Takeda. A.A. reports conference travel support and/or honoraria from BioCryst, CSL Behring, Intellia, and Takeda, and clinical trial support from Astria, CSL Behring, Ionis, KalVista, Octapharma, Pharvaris, and Takeda, outside of the submitted work. A.B. reports research funding from Ionis, Astria, and Intellia, and advisory boards with CSL Behring, Ionis, Pharvaris, Intellia, KalVista, Astria, Takeda. S.B. reports speaker and/or advisor fees from Astria, BioCryst, CSL Behring, Ionis, KalVista Pharmaceuticals, Pharvaris, and Takeda, and research funding from CSL Behring and Takeda. Chair of the Canadian Hereditary Angioedema Network. I.B-G. is or recently was a speaker, advisor, engaged in research and educational projects, and/or received research and consultancy grants from Takeda, CSL Behring, Pharming, KalVista, Pharvaris, and BioCryst. M.B. reports conference travel support and research/advisory fees from Takeda, KalVista, and CSL Behring. H.B.B. reports no conflicts in relation to this manuscript. T.C. is or recently was a speaker, advisor, engaged in research and educational projects, received research grants and/or received funding to attend conferences and educational events from Astria, BioCryst, CSL Behring, IONIS, KalVista, Novartis, Otsuka, Pharming, Pharvaris, and Takeda. She is a researcher in the Hospital La Paz Institute for Health Research (IdiPAZ) program for promoting research activities. M.C. received grant research support and/or speaker/consultancy fees from BioCryst, CSL Behring, KalVista, Novartis, Pharming, Pharvaris, Sanofi, Shire-Takeda, and SOBI. A.J.C. reports no conflicts in relation to this manuscript. D.M.C reports speaking and/or consultancy fees from Astria, BioCryst, CSL Behring, Intellia, Ionis, KalVista, Pharming, Pharvaris, and Takeda. D.C. reports no conflicts in relation to this manuscript. C.D. reports no conflicts in relation to this manuscript. A.F. has received honoraria from CSL Behring, Takeda and Torii, and a consulting fee from KalVista. M.H. has received speaker/consultancy fees for BioCryst, CSL Behring, KalVista, Pharvaris, Takeda, and Torii. C.H.K. reports speaking and/or consultancy fees from CSL Behring, Takeda, BioCryst, KalVista, Pharvaris, and Intellia, outside of the submitted work. P.H.L. reports speaking and/or consultancy fees from CSL Behring, KalVista, Pharvaris, and Takeda, outside of the submitted work. H.L. has collaborated in research and educational projects with, served as a speaker or advisor for, or received educational support from the following companies: CSL Behring, Intellia, KalVista, Pharvaris, Takeda. J.P. reports educational grant support from Takeda and speaking or advisory board fees from Astria, BioCryst, CSL Behring, KalVista, Pharvaris, and Takeda. F.P. reports speaking and/or consultancy fees from CSL Behring, Pharvaris, and Takeda. A.R. reports advisory boards and consultancy from BioCryst, CSL Behring, Ionis, Pharming, Pharvaris, and Takeda and received speaker’s honoraria from BioCryst, CSL Behring, and Takeda. Received research funding from BioCryst, CSL Behring, Ionis, Pharvaris, Shulov, and Takeda (formerly: Shire). B.R. reports conference travel support from CSL Behring, Octapharma, Takeda, and clinical trial support from CSL Behring. C.N.S. reports no conflicts in relation to this manuscript. A.Z. received speaker/consultancy fees from Astria, BioCryst, CSL Behring, KalVista, Otsuka, Pharming, Pharvaris, and Takeda. M.Mr. reports grants or speaker/advisor fees from Astria, BioCryst, CSL Behring, KalVista, Pharvaris and Takeda.

Figures

**Fig. 1**
Algorithm for diagnosis of recurrent angioedema with normal C1 inhibitor. *Family history may be an unreliable marker of HAE as detailed in the text

**Fig. 2**
Treatment efficacy for HAE-FXII from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-FXII patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-FXII patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response

**Fig. 3**
Pretreatment efficacy for HAE-PLG from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-PLG patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-PLG patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response

**Fig. 4**
Treatment efficacy for HAE-UNK from the HCT survey. Expert physician ratings of the efficacy of each medication are shown along with the number of HAE-UNK patients treated by each expert. Each blue square represents the report by one expert. The size of the square is proportional to the number of HAE-UNK patients assessed, which is indicated next to it. The larger the square, the more patients showed the indicated response

See this image and copyright information in PMC

References

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Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment

Affiliations

Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment

Authors

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Abstract

Conflict of interest statement

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