MS1 Hereditary Hemorrhagic Telangiectasia

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Author:
jknell
ID:
206926
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MS1 Hereditary Hemorrhagic Telangiectasia
Updated:
2013-03-14 16:09:39
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Multisystem disorders
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hereditary hemorrhagic telangiectasia
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  1. Hereditary Hemorrhagic Telangiectasias
    name = disease
    • Genetic, inherited (Autosomal dominant)
    • Patients bleed
    • Arteriovenous malformations
  2. HHT
    epidemiology
    • Most common and most important hereditary disease of the vasculature across multiple organs
    • Homozygosity for HHT genetic defects is fatal in utero
    • Incidence varies by region/race
    •      -1:16,500 in Vermont
    •      -1:5,000 to 8,000 in Europe and Japan
    •      -1:1,330 in Afro-Caribbean in Curacao and Bonaire
  3. HHT
    Curacao criteria
    • -Autosomal dominant disorder
    • -Epistaxis
    • -Mucocutaneous telangiectasias
    • -Visceral AVM's (especially lung, brain, liver)

    • Criteria:
    • -"Definite" if 3-4 present
    • -"Suspected" if 2 present
    • -"Unlikely" if 1 is present
  4. HHT
    Manifestation
    • Birth: no stigmata
    • Epistaxis begins in chilhood
    • Visceral AVMs usually start developing during teens
    • Cutaneous telangiectasias usually progressive, start in 20s
    • Presentation: 70% have signs/sx by 16, >90% by age 40
  5. HHT
    Mucocutaneous telangiectasias
    • Frequently suggest diagnosis
    • most commonly occur on face, lips, tongue, buccal mucosa, palate, fingertips
    • Presents after age 20, progress (in number and size)
    • May bleed, but rarely a significant amount
  6. HHT
    Epistaxis
    • Most common feature, most troubling
    • Multiple times daily, lasts for hours
    • Frequently require blood transfusions or IV iron
  7. Pulmonary AVM in HTT patient
  8. HHT
    Pulmonary AVM's
    • Present in ~50% of HHT pts
    • 70% of Pulmonary AVM patients are HHT pts
    • Presentation: range from diffuse telangiectasias to large, complex, structures
    • 95% of feeding vessels are from pulmonary arteries (good thing, low pressure)
  9. HHT
    Complications of PAVMs
    • R-L shunt:
    • -Hypoxemia
    • -TIA
    • -Stroke
    • -Brain abscess

    • Hemoptysis
    • Hemothorax
    • Increase in size/number over time
  10. Cerebral AVMs
  11. HHT
    Cerebral AVM
    • Affect 10% in HHT
    • Usually silent
    • Can produce HA, seizures, ischemia, hemorrhage
    • Heaptic AVM
    • -Occurs in 30% of HHT
    • -Usually clinically silent
    • -Occasionally can cause high output failure, portal hypertension, biliary disease
  12. HHT
    GI bleeding 
    • Recurrent GI bleeding occurs in ~1/3
    • May be macroscopic or occult (Fe deficient anemia)
    • Usually in patients >40yrs
    • Can be due to telangiectasias or larger AVMs thoughout GI tract
    • *hard to identify the source
  13. Pulmonary Arterial Hypertension in HHT
    • 5-10% of HHT pts have PAH
    • Type 1 PAH (ALK1, endoglin, BMPRII)
  14. Treatment of clinical problems
    • Epistaxis: surgery
    • Pulmonary AVMs: embolotherapy
    • CNS AVMs: surgery
    • GI: local therapy, not that effective
    • Hepatic: liver transplant
    • *Always check: brain, lungs
  15. HHT
    Pathophysiology
    • Autosomal dominant inheritance
    • Genes:
    • -HHT1 - chromosome 9
    • -HHT2 - chromosome 12 (determined to be activin receptor-like kinase 1 (ALK-1)
    • -HHT3 - chromosome 5
    • -HHT4 - chromosome 7

    • Juvenile polyposis/HHT syndrome maps to chromosome 18:
    • -Smad4
    • ->10 hamartomatous juvenile colonic polyps, with potential for malignant transformation
  16. HHT
    Genotype to phenotype
    • Genes generally present with a similar phenotype
    • HHT1 → lots of pulmonary AVMs, early nosebleeds
    • HHT2 → fewer pulmonary AVMs, increased risk of pulmonary hypertension
  17. Endoglin
    • Transmembrane accessory receptor for TGF-β 
    • Predominantly expressed on angiogenic blood vessels and essential during angiogenesis
    • Endoglin key in the balance of ALK1 and ALK5 signaling to regulate endothelial cell proliferation:
    •      -Required for efficient TGF-β/ALK1 signaling
    •      -indirectly inhibits TGF-β/ALK5 signaling
  18. TGF-β/ALK signaling
    angiogenesis and endothelium



  19. Vascular Endothelial Growth Factor
    (VEGF)
    • 7 members
    • VEGF-A plays most critical role in angiogenesis
    •      -induces differentiation and fenestration
    • Supports EC survival
  20. HHT labs
    VEGF, TGF-β
    • VEGF plasma levels are elevated
    • TGF-β are also elevated
  21. Treatment of HHT
    • VEGF antagonist: Bevacizumab
    • -Dramatically decreased transfusion requirements
    • -Increased CO
    • -Performance status improved

    *Some evidence; used off-label

    • Side effects:
    • - many adverse reactions: proteinuria, cardiac ischemia/infarct, GI bleeding, Thrombosis, leukoencephalopathy...
  22. Bevacizumab
    data, uses
    • Dramatic improvements, but recrudescence of disease ~ a year after treatment stopped
    • Used to treat epistaxis effectively (topically)
    • Used as adjunct to other therapies when lung, CNS or other organs involved
    • Currently in phase II trials; used off label for serious hepatic or GI disease

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