What is HHT (Hereditary Hemorrhagic Telangiectasia)?
HHT is an autosomal dominant genetic bleeding disorder affecting approximately 1 in 5,000 people, characterized by abnormal blood vessel formations (vascular malformations) that cause recurrent bleeding and life-threatening complications from abnormal shunting of blood. 1
Genetic Basis
HHT results from loss-of-function mutations in genes involved in the BMP (bone morphogenetic protein) signaling pathway 2:
- ENG (endoglin) - causes HHT type 1
- ACVRL1 (activin receptor-like kinase-1) - causes HHT type 2
- SMAD4 - causes juvenile polyposis-HHT overlap syndrome
- GDF2 - less common cause
In 97% of patients with definite clinical HHT, a causative mutation is identified in one of these genes 1. Recent genetic analysis suggests HHT may be significantly underdiagnosed, with true prevalence potentially 2-12 times higher than current estimates (between 2.1 and 11.9 per 5,000 people) 3.
Clinical Manifestations
Mucocutaneous Telangiectasias
Small, fragile blood vessel malformations appear on:
- Nasal mucosa (causing epistaxis)
- Lips, tongue, oral cavity
- Face and fingers
- Gastrointestinal tract
These telangiectasias have age-related expression, becoming more prominent over time 1.
Visceral Arteriovenous Malformations (AVMs)
Pulmonary AVMs cause:
- Right-to-left shunting
- Risk of ischemic stroke (paradoxical embolism)
- Brain abscess
- Hypoxemia
Hepatic AVMs cause:
- Left-to-right shunting
- High cardiac output heart failure
- Portal hypertension
- Biliary disease
Cerebral AVMs cause:
- Intracranial hemorrhage
- Seizures
- Neurological deficits
Bleeding Complications
Epistaxis (nosebleeds) is the hallmark symptom:
- Occurs in >90% of adults with HHT 4
- Can last hours per day
- Causes significant psychosocial morbidity and social isolation
- Age-related onset and progression
Gastrointestinal bleeding from intestinal telangiectasias develops later in life.
Iron deficiency anemia develops in nearly half of all patients due to chronic blood loss 5.
Diagnosis
Curaçao Criteria (upheld in international guidelines) 1:
A definite diagnosis requires 3 of 4 criteria:
- Spontaneous, recurrent epistaxis
- Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, nose)
- Visceral AVMs (pulmonary, hepatic, cerebral, spinal)
- First-degree family member with HHT
Genetic testing is recommended primarily for asymptomatic persons from families with known HHT to enable appropriate screening and preventive treatment 1.
Clinical Significance
Underdiagnosis Problem
HHT is frequently underdiagnosed with long diagnostic delays 1. This is critical because:
- Early diagnosis allows screening for life-threatening visceral AVMs
- Preventive treatment can be initiated
- At-risk family members can be evaluated
- Appropriate management reduces morbidity and mortality
Thrombotic Risk
Despite being a bleeding disorder, HHT patients have increased risk of venous thromboembolism (VTE), particularly those over 65 years (incidence 45.1/1,000 patient-years vs 11.6/1,000 in younger patients) 6. Underuse of thromboprophylaxis during hospitalization contributes to this excess risk.
Modern Management Paradigm
The treatment landscape has fundamentally shifted from purely procedural interventions to include systemic medical therapies 4. The Second International HHT Guidelines (2020) now recommend:
- Systemic antiangiogenic therapies (targeting VEGF excess)
- Antifibrinolytic agents (tranexamic acid)
- Iron replacement for anemia management
- Screening protocols for visceral AVMs
- Interventional radiology for AVM treatment 7
These systemic therapies are now recommended on equal standing with surgical treatments for bleeding control 4.
Key Clinical Pitfalls
Do not dismiss recurrent epistaxis as trivial - it is the sentinel symptom requiring full HHT evaluation.
Do not withhold anticoagulation when indicated - the thrombotic risk may outweigh bleeding risk in certain clinical scenarios, requiring individualized assessment 6.
Do not delay screening for visceral AVMs - pulmonary AVMs can cause stroke or brain abscess; early detection and treatment prevents these catastrophic complications.
Do not assume HHT is as rare as traditionally taught - it is likely the second most common inherited bleeding disorder after von Willebrand disease and is significantly underdiagnosed 5.