New diagnostic biomarkers and new therapeutic targets for the minority disease Lymphangioleiomyomatosis

A study by IDIBELL and the ICO, with the collaboration of the Spanish LAM Association, has detected that patients suffering from Lymphangioleiomyomatosis have elevated plasma levels of a histamine derivative, which could be used for the diagnosis of the disease. The study, published in the journal EMBO Molecular Medicine, demonstrates that inhibition of the histamine pathway stops the disease progression in mice. Alliance between patients, researchers and healthcare and research centers to advance the care of a minority disease.

Imatge grup

Lymphangioleiomyomatosis (LAM) is a rare disease that mainly affects women and is characterized by abnormal proliferation of epithelial and spindle cells. Although it is not considered a cancer itself, these cells have the ability to metastasize. Additionally, this hyperproliferation can damage lung tissue and lead to severe respiratory failure.

The breast cancer research group of the Bellvitge Biomedical Research Institute (IDIBELL) and the ProCURE program of the Catalan Institute of Oncology (ICO), led by Dr. Miquel Àngel Pujana, has identified different products of histamine transformation, an important signaling molecule involved in multiple physiological functions, as possible biomarkers to improve the diagnosis of the disease, and in turn, also as possible new therapeutic targets.

The current diagnosis of LAM is critical, since it presents a high heterogeneity of symptoms and numerous similarities with other pathologies. Until now, the differential diagnosis was made through the plasma levels of VEGF-D. However, it is an unclear biomarker due to the high interindividual variability, and on many cases, it was necessary to perform a lung biopsy to confirm the diagnosis.

In the article published in EMBO Molecular Medicine, the scientists have identified that LAM patients have elevated plasma levels of one of the main products of histamine transformation, MIAA, and that, therefore, it could be used as a novel biomarker. Carmen Herranz, researcher at IDIBELL and first author of the work comments: “The plasma levels of MIAA are independent of the levels of the biomarker used so far, VEGF-D, and, therefore, the most interesting option would be to use the combination of both to make a reliable diagnosis of LAM.”

There are patients who do not tolerate the usual treatment for LAM with rapamycin well, some even continue to lose lung function despite therapy. In this study, researchers have detected that, in animal models, the inhibition of the histamine pathway stops the disease progression. Dr. Miquel Àngel Pujana explains that “treatment with antihistamines, drugs already approved for other pathologies, is beneficial as monotherapy and could even have a synergistic effect with rapamycin.” And he adds: “We have now started a clinical trial to determine the efficacy and safety of dual treatment with rapamycin and loratidine, a common antihistamine.”


Next steps

The published study has led to a multicenter phase II clinical trial led by Dr. María Molina, also a researcher at IDIBELL and the head of the Pulmonary Interstices Functional Unit of the Bellvitge University Hospital. This trial is funded by the Carlos III Health Institute and will begin shortly with the objective of evaluating the safety and benefits of the combination of rapamycin and the antihistamine loratadine in the treatment of LAM. Likewise, the newly identified biomarkers of the disease will be evaluated.

This work has been possible thanks to the participation of LAM patients and the support obtained with the collaboration agreement established between the ICO and IDIBELL, and the Spanish LAM Association (AELAM).

On the other hand, researchers from the Rovira i Virgili University – IISPV (Dr. Oscar Yanes), clinical managers of the LAM in different state referral centers (Dra. María Molina-Molina, Bellvitge University Hospital; Dr. Berta Sáez and Dr. Antonio Román, Vall d’Hebron University Hospital; Dr. Claudia Valenzuela and Dr. Julio Ancochea, La Princesa University Hospital; Dr. Piedad Ussetti and Dra. Rosalía Laporta, Puerta de Hierro University Hospital Dr. José A. Rodríguez-Portal, Virgen del Rocío University Hospital, and Dr. Álvaro Casanova, Henares University Hospital), and researchers from the ILD Center of Excellence St. Antonius Hospital of the Netherlands, of the National Lung Disease Research Institute of Poland, and the National Center for Lymphangioleiomyomatosis of the United Kingdom.



The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).


Reference article

Carmen Herranz, Francesca Mateo, Alexandra Baiges, […] Miquel A Pujana. Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis. EMBO Mol Med  . 2021 Aug 11;e13929.

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