Hereditary Hemorrhagic Telangiectasia: Genetics, Pathophysiology, Diagnosis, and Management

Abstract

Hereditary hemorrhagic telangiectasia is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. As complications, it presents vascular malformations in organs such as the lung, liver, digestive tract, and brain. Currently, diagnosis can be made using the Curaçao criteria or by identifying the affected gene. In recent years, there has been an advance in the understanding of the pathophysiology of the disease, which has allowed the use of new therapeutic strategies to improve the quality of life of patients. This article reviews some of the main and most current evidence on the pathophysiology, clinical manifestations, diagnostic approach, screening for complications, and therapeutic options, both pharmacological and surgical.

Keywords: VEGF; angiogenesis; arteriovenous malformations; epistaxis; hereditary hemorrhagic telangiectasias; telangiectasias.

Figure 1

Main pathways involved in the pathophysiology of HHT. Members of the TGF-β family (mainly BMP9 and 10), bind to specific cell surface type I (R-I) and type II (R-II) receptors. These receptors exhibit serine/threonine kinase activity. The main R-I receptors involved in this pathway are ALK-1 and ALK-5. On the other hand, R-II receptors include TβRII, ActRII, BMPRII. Endoglin is an auxiliary receptor that associates with the ligand, ALK-1/R-II complex, potentiating its action. A soluble form of endoglin (sol-eng) can be generated by proteolysis of the membrane-bound receptor that can sequester ligands (BMP9 or 10) and thus modulate their binding to R-I/R-II receptors. The association between R-I (either ALK-1 or ALK-5) with R-II determines the specificity of ligand signaling. Upon ligand binding, R-II transphosphorylates R-I, which then propagates the signal by phosphorylating the receptor-regulated Smad family of proteins. Once phosphorylated, R-Smads form heteromeric complexes with a cooperating homologue called Co-Smad (Smad4) and translocate to the nucleus where they regulate the transcriptional activity of target genes. In endothelial cells, ALK1 and ALK5 activate signaling two different pathways via Smad1, 5, 8 (ALK1) or Smad2, 3 (ALK5), respectively. The first one promotes transcription of genes related to angiogenesis. The second promotes transcription of genes related to repairing phase. Endoglin, ALK1, Smad4, and BMP9 proteins are encoded by ENG, ACVRL1, MADH4, and GDF2 genes respectively. ActR, activin receptor; BMP, bone morphogenetic protein; BMPR, BMP receptor [14,15,16].

Figure 2

Pulmonary AVMs. AngioCT reconstruction of the thorax of a patient with HHT from the systemic and minority disease unit of the Hospital Ramón y Cajal, with the patient’s consent. Note the AVM located in the left lower lobe (red arrows).