Makindo Medical Notes

Hereditary Hemorrhagic Telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is a rare autosomal dominant genetic disorder characterized by abnormal blood vessel formation (telangiectasia) throughout the body. These fragile blood vessels are prone to bleeding and can affect various organs, including the skin, mucous membranes, lungs, liver, and brain. Early diagnosis and management are essential to prevent and address potential complications such as hemorrhagic strokes and severe gastrointestinal bleeding.

About

• Definition: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder that leads to the development of abnormal blood vessels (telangiectasia) in the skin and mucous membranes, as well as in internal organs.
• Genetics: HHT is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is necessary to cause the disorder.
• Vascular Involvement: Telangiectasia typically present on the skin and mucous membranes but can also involve the lungs, liver, and brain, leading to complications like arteriovenous malformations (AVMs).
• Family History: A positive family history is common, with affected individuals often having a parent, sibling, or child with HHT.
• Prevalence: HHT is rare, affecting approximately 1 in 5,000 to 8,000 individuals globally.

Studies indicate that the prevalence of brain arteriovenous malformations (AVMs) in HHT patients is around 10.4%, with no significant gender differences. Additionally, pulmonary AVMs are highly prevalent, occurring in the majority of individuals with HHT.

Aetiology

• Angiogenesis Disorder: HHT is caused by mutations that disrupt normal blood vessel formation, resulting in fragile and malformed vessels.
• Genetic Mutations: Commonly associated with mutations in the ACVRL1, ENG, and SMAD4 genes.
• Genotype-Phenotype Correlation:
  • HHT1: Caused by mutations in the ENG gene, associated with a higher prevalence (13.4%) of brain AVMs.
  • HHT2: Caused by mutations in the ACVRL1 gene, with a lower prevalence (2.4%) of brain AVMs.
  • Juvenile Polyposis/HHT Syndrome: Caused by mutations in the SMAD4 gene, linking HHT with juvenile polyposis.

Aetiology of Stroke in HHT

• Hemorrhage from Cerebral AVMs: Fragile blood vessels in the brain can rupture, leading to hemorrhagic strokes.
• Paradoxical Embolism: Rare instances where emboli bypass the pulmonary circulation through pulmonary AVMs, potentially causing ischemic strokes.
• Vessel Fragility: Lack of contractile elements in blood vessels increases the risk of severe bleeding, particularly in gastrointestinal tracts leading to GI bleeds.

Most individuals with pulmonary arteriovenous malformations (PAVMs) have HHT, making it a critical component of the disease's clinical presentation.

Clinical Features

• Epistaxis: Recurrent nosebleeds are the most common symptom, occurring in the majority of individuals by adulthood.
• Gastrointestinal Bleeding: May present as haematemesis, melaena, or iron deficiency anaemia, particularly in patients over 50 years old.
• Neurological Complications: Increased risk of haemorrhagic stroke due to cerebral AVMs and embolic stroke from paradoxical embolism.
• Mucocutaneous Telangiectasia: Small, dilated blood vessels visible on the skin, oral cavity, and nose.
• Pulmonary AVMs: Can rupture, leading to haemoptysis (coughing up blood).

Clinical Signs

Types of HHT

• Type 1: Caused by mutations in the ENG gene, associated with a 13.4% prevalence of brain AVMs.
• Type 2: Caused by mutations in the ACVRL1 gene, associated with a 2.4% prevalence of brain AVMs.
• Juvenile Polyposis/HHT Syndrome: Caused by mutations in the SMAD4 gene, linking HHT with juvenile polyposis.

Differential Diagnosis

• Vasculitis: Conditions like granulomatosis with polyangiitis can present with telangiectasia and systemic symptoms.
• Thrombocytopenia: Low platelet counts can lead to recurrent bleeding similar to HHT.
• Telangiectasia in Chronic Liver Disease: Presents as spider angiomas with central cores and radiating vessels, often associated with liver dysfunction.

Diagnostic Clinical Criteria

Criterion	Description
Epistaxis	Spontaneous and recurrent nosebleeds.
Mucocutaneous Telangiectasia	Multiple telangiectasias at characteristic sites (lips, oral cavity, fingers, and nose). Lesions are blanchable, pink-red, and range from pinpoint to pinhead in size. Occasionally, they appear as 2-5 mm macules or "spidery" purple lesions.
Visceral AVMs	Pulmonary Cerebral Hepatic Gastrointestinal (GI) Spinal
Family History	A first-degree relative with a confirmed HHT diagnosis.

The clinical diagnosis of HHT is categorized as follows:

• Definite: When three or more diagnostic criteria are present.
• Possible or Suspected: When two diagnostic criteria are present.
• Unlikely: When fewer than two diagnostic criteria are present.

Note: These diagnostic criteria were established for adults and may not be as reliable when applied to children.

Investigations

• Laboratory Tests:
  • Full Blood Count (FBC) to exclude iron deficiency anaemia from GI blood loss.
  • Ferritin and iron studies.
  • Inflammatory markers: ESR, CRP.
  • Urea & Electrolytes (U&E), Liver Function Tests (LFTs).
  • Vitamin B12 and folate levels.
• Imaging Studies:
  • Brain imaging (CT/MRI/MRA) if stroke is suspected.
  • Chest X-ray or lung CT to identify pulmonary AVMs.
  • Cerebral angiography for suspected AVMs. The Spetzler-Martin grade for HHT-related lesions is ≤2 in nearly 90% of patients.
  • Bubble echocardiogram for screening pulmonary AVMs, followed by a CT pulmonary angiogram if positive.
  • Colonoscopy and upper endoscopy, possibly with capsule endoscopy, to investigate GI bleeding. Patients with SMAD4 mutations may also require screening for polyps.
• Genetic Testing: To confirm the genetic subtype of HHT in affected individuals and family members, facilitating appropriate screening and preventive treatment.

Management

• Emergency Management:
  • Follow the ABC protocol (Airway, Breathing, Circulation) and manage any acute hemorrhagic stroke promptly.
  • Immediate management of upper GI bleeding may require transfusions and endoscopic interventions.
• Specialist Referrals:
  • ENT Specialist: For management of epistaxis, typically treated with laser ablation for mild to moderate cases.
  • Gastroenterologist: For GI bleeds and iron replacement therapy for anaemia.
  • Rheumatologist: If there are signs of joint involvement or other systemic manifestations.
  • Interventional Neuroradiologist: For closure of pulmonary AVMs. PAVMs with a feeding artery greater than 1-3 mm should be considered for treatment via transcatheter embolization.
• Medical Therapies:
  • Avoid antithrombotic drugs to reduce the risk of bleeding.
  • Use antifibrinolytic agents such as tranexamic acid in select patients to manage bleeding episodes.
  • Iron supplementation for patients with iron deficiency anaemia.
• Genetic Counseling: Recommended for affected individuals and their families due to the hereditary nature of HHT.
• Management of AVMs:
  • Surgical and nonsurgical treatments for cerebral AVMs have similar long-term outcomes and should be tailored to individual cases.
  • Interventional neuroradiology is preferred for closing pulmonary AVMs through transcatheter embolization.

Prognosis

• HHT is a chronic condition with variable severity; many individuals lead normal lives with appropriate management.
• Complications such as hemorrhagic strokes and severe GI bleeding can impact prognosis significantly.
• Early detection and treatment of AVMs and other vascular malformations can prevent serious outcomes and improve quality of life.

References

• Prevalence and Characteristics of Brain Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia: A Systematic Review and Meta-Analysis
• MR of Hereditary Hemorrhagic Telangiectasia: Prevalence and Spectrum of Cerebrovascular Malformations
• Surgical vs. Nonsurgical Treatment for Brain AVMs in Hereditary Hemorrhagic Telangiectasia
• Hereditary Hemorrhagic Telangiectasia: Diagnosis, Management, and Pathogenesis
• Hereditary Hemorrhagic Telangiectasia - NCBI Bookshelf
• Merck Manuals - Male Urethral Catheterization