Hereditary hemorrhagic telangiectasia (HHT / Osler-Weber-Rendu)

What changes during this transition

HHT (Osler-Weber-Rendu) is an autosomal dominant vascular dysplasia driven by germline mutations in TGF-β/BMP signaling genes — ENG (HHT1, ~50% of cases), ACVRL1/ALK1 (HHT2, ~40%), SMAD4 (HHT3, ~2%; juvenile polyposis-HHT overlap), and GDF2/BMP9 (HHT4, rare). The disease driver is endothelial dysfunction producing fragile dilated vessels that lack proper capillary beds — telangiectasias on lips, oral mucosa, fingers, and tongue plus arteriovenous malformations (AVMs) in the lungs (30-50% of patients), liver (30-70%), brain (10-20%), and spinal cord (rare). GI telangiectasias drive chronic occult bleeding and iron-deficiency anemia in many adults. Diagnosis follows the updated 2020 Curaçao Criteria: spontaneous recurrent epistaxis (universal, mean onset around age 12, near-universal by 21), multiple telangiectasias at characteristic sites, visceral AVMs, and first-degree family history — three out of four = definite, two = possible. Pulmonary AVMs (PAVMs) carry the highest acute risk: right-to-left shunt enables paradoxical embolization, so even small PAVMs (feeding artery ≥3mm) require interventional-radiology coil embolization to prevent stroke and brain abscess. PAVM screening uses contrast bubble echocardiography every 5-10 years lifelong. Cerebral AVMs (~10-20% of patients) carry hemorrhagic stroke risk and are screened via MRI/MRA per center protocol. Hepatic AVMs can drive high-output cardiac failure, portal hypertension, and biliary cholangiopathy. The epistaxis management ladder runs humidification → topical agents → laser → embolization → septodermoplasty → Young's procedure (nostril closure) → systemic anti-angiogenic therapy. Iron supplementation and transfusions manage chronic anemia. Antifibrinolytics (tranexamic acid) help some patients. **The 2024 paradigm shift**: intravenous bevacizumab (Avastin, anti-VEGF monoclonal) received FDA approval in June 2024 as the first disease-modifying therapy for HHT, based on international expert consensus and ATAC trial data. It's transformative for severe transfusion-dependent epistaxis, GI bleeding, and high-output cardiac failure from hepatic AVMs. The mechanism — VEGF blockade suppresses the angiogenic signaling that maintains and worsens HHT vasculature — is the load-bearing point for any peptide conversation in this context. Pregnancy is high-risk: PAVMs can rupture and cause maternal death, so PAVM screening and treatment before pregnancy is high-priority, and pregnancies are managed by maternal-fetal-medicine specialists familiar with HHT. Estrogen drives some worsening. Genetic testing and first-degree family cascade screening are standard. International HHT Foundation (Cure HHT) maintains patient advocacy and care-center networks; the 2020 international guidelines update (Faughnan et al.) is the practice anchor. **The editorial substrate for peptides**: HHT is one of the cleanest peptide × disease mechanistic contradictions in the Juno library. BPC-157 and TB-500 — both community-marketed as pro-angiogenic VEGF-driven 'healing peptides' — are mechanistically opposite to bevacizumab, the new standard of care. No human HHT dataset exists for either peptide, and the mechanistic contradiction earns Tier 2 status not because there's evidence of harm in HHT but because the pharmacology of these peptides is structurally opposed to the disease-modifying therapy specialists now use. GH-axis peptides (CJC-1295, tesamorelin, ipamorelin) raise IGF-1, which has uncharacterized effects on endothelial biology in genetically dysplastic vasculature and on the bevacizumab-suppressed VEGF axis. General-aging supplements (NMN) don't engage HHT biology. No peptide currently in the Juno library has an evidence base supporting its addition to HHT care — substrate exists for honest /ask answers when users ask the question, not to surface peptides as discovery options against a disease with active anti-angiogenic standard of care. Care belongs with HHT centers of excellence (Cure HHT maintains the directory), interventional radiology for PAVM management, and maternal-fetal medicine for pregnancy planning. Sixty-first deliberate non-elevation.