Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

1
Hereditary Hemorrhagic Telangiectasia
(Osler-Weber-Rendu Syndrome)

• Andrew Avery
• A.M. Report
• 06/26/09

2
Introduction

• HHT is an autosomal dominant genetic disorder
  that leads to vascular malformations
• First recognized in the 19th century as a
  familial disorder with abnormal vascular
  structures causing bleeding from the nose and
  gastrointestinal tract
• HHT is characterized by telangiectatic lesions of
  the nose, lips, and visceral organs including the
  liver, spleen, gastrointestinal tract, lungs,
  brain, and spinal cord

3
Epidemiology

• Incidence in Europe and Japan at rates between
  15000 and 18000 but widely variable in other
  regions
• More frequently occurs in whites

4
Pathophysiology

• Mutations in at least four genes can cause HHT
• The two major disease genes responsible for HHT
  are on chromosome 9 (ENG, protein product
  endoglin) and chromosome 12 (ACVRL1, protein
  product activin receptor-like kinase 1, ALK-1)
  designated HHT1 and HHT2, respectively

5
Pathophysiology

• HHT results from endoglin or ALK-1
  haploinsufficiency (ie, lack of sufficient
  protein for normal function)
• ALK-1 is a transforming growth factor (TGF)-beta
  superfamily type I receptor, and endoglin
  associates with different signaling receptors and
  can modify TGF-beta-1 signaling
• Thus, it is thought that abnormal vessels in HHT
  probably develop because of aberrant TGF-beta
  signaling at some stage during vascular
  development

6
Pathophysiology

• HHT1 pulmonary and cerebral AVMs are more common
  
• HHT2 hepatic AVMs are more common
• However, understanding whether a pt has an
  endoglin or ALK-1 mutations does not allow a
  strong prediction of the likely course of HHT,
  since all features of HHT can be seen in both
  HHT1 and HHT2.

7
Clinical Features

• Majority of patients with HHT experience only
  epistaxis, mucocutaneous telangiectasia, and a
  tendency to develop iron deficiency anemia
  secondary to the blood loss
• In pts who do not present spontaneously to a
  clinician before the age of 60 years, there is no
  excess mortality
• There is significant morbidity and mortality in
  younger patients, predominantly attributed to the
  consequences of visceral involvement

8
Clinical Features

• Epistaxis-most common manifestation. Severity is
  widely variable
• GI Bleeding-occur in 1/3 of pts telangiectasia
  more common in the stomach or duodenum, but can
  occur anywhere
• Mucocutaneous telangiectasia- occur in the skin
  and buccal mucosa of about 75 percent of
  individuals, typically presenting after the age
  of 20, and increasing in size and number with
  age mostly occur on the face, lips, tongue,
  buccal mucosa, fingertips, and dorsum of the
  hand, but can occur elsewhere

9
Colon Angiodysplasia
10
Superficial telangectasias
11
Pulmonary AVMs

• Definition thin walled abnormal vessels that
  replace normal capillaries between the pulmonary
  arterial and venous circulations
• Provide a direct capillary-free communication
  between the pulmonary and systemic circulations
• The majority of pulmonary AVM patients have no
  respiratory symptoms
• Only 1/3 of affected individuals exhibited
  physical signs indicating a substantial
  right-to-left shunt (eg, cyanosis, clubbing,
  polycythemia)

12
Complications of Pulmonary AVMs

• Neurological sequelae 2/2 to paradoxical emboli
  are most common and include both catastophic
  embolic cerebral events (e.g. cerebral abscess
  and embolic stroke) and TIAs
• Hemorrhage may occur vessels in a bronchus or the
  pleural cavity, causing hemoptysis or hemothorax
• High-output heart failure may develop in the
  presence of marked shunting arterial blood to the
  venous circulation

13
Pulmonary AVMs
14
Cerebral AVMs

• Cerebral AVMs affect approximately 10 percent of
  HHT patients (usually silent)
• May lead to headache, seizures, hemorrhage, or
  ischemia of the surrounding tissue (due to a
  steal effect)
• One large observational study showed that HHT pts
  under the age 46 years were 23 times more likely
  to have a stroke than their counterparts in the
  general population

15
Cerebral AVMs
16
Hepatic AVMs

• Silent hepatic involvement occurs in up to 30
  percent of patients with HHT
• Symptoms are much less frequent and include
  high-output heart failure, portal hypertension,
  and biliary disease
• Large AVMs between the hepatic artery and vein
  can cause a significant left-to-right shunt with
  steal syndromes that can cause angina
• Portal hypertension and hepatic encephalopathy,
  particularly after episodes of gastrointestinal
  bleeding, may result from shunts between the
  hepatic artery and portal vein

17
Diagnostic Criteria

• Spontaneous and recurrent epistaxis
• Multiple mucocutaneous telangiectasias
• Visceral involvement (eg, gastrointestinal,
  pulmonary, cerebral, or hepatic AVMs)
• A first-degree relative with HHT
• -three or four criteria-gtdefinite two criteria
  -gtsuspected none-gtunlikely
• The diagnosis may be confirmed by formal genetic
  testing for mutations involving endoglin, ALK-1,
  or SMAD4

18
Physical Exam

• When HHT is suspected, PE focuses on searching
  for teleangiectasias, which are usually most
  commonly located on the digits, pinna, bridge of
  the nose, tongue or palate.
• Auscultation of the liver for presence of
  bruits, and heart for high-output cardiac failure
  should be performed
• A detailed neurological examination should foucs
  on uncovering prior evidence of a stroke

19
Management

• Epistaxis Treatments are generally directed to
  patients either experiencing massive hemorrhages
  or experiencing daily epistaxis, and include
  laser ablation, arterial ligation,
  septodermoplasty, and unilateral or bilateral
  surgical closure of the nostrils
• GI Bleed Repeated endoscopic ablation of
  gastrointestinal lesions may be used to control
  bleeding in the short term. Surgery has limited
  success due to recurrent disease, but may be
  useful for emergency control of hemorrhage from
  discrete lesions, as may embolization

20
Management

• GI Bleed Estrogen-Progesterone has been found to
  be useful in managing recurrent bleeds role of
  antifibrinolytics is being investigated
• Iron Deficiency Anemia Pts with minimal degrees
  of bleeding can receive oral iron therapy.
  However, bleeding may be severe enough to require
  blood transfusions and/or parenteral iron therapy

21
Management of AVMs

• Pulmonary AVMs embolotherapy is recommended
• Cerebral AVMs may be treated with embolectomy,
  surgical removal, or stereotactic radiotherapy
• Hepatic AVMs if medical management fails, liver
  transplantation is the treatment of choice.