Hereditary Hemorrhagic Telengectasia

1 What is Hereditary Hemorrhagic Telengectasia?

Hereditary hemorrhagic telengectasia, also known as Osler-Weber Rendu disease is a genetically inherited disorder, inherited in an autosomal dominant manner.

Mutations in the ACVRL1, ENG, and SMAD4 genes cause hereditary hemorrhagic telangiectasia.

The primary target organs of the disease are:

  • lungs,
  • liver,
  • brain which are affected by abnormal blood vessel formation.

The disease typically affects skin and mucous membrane. Forms of hereditary hemorrhagic telangiectasia include type 1, type 2, type 3, and juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome.

The disease may present as nose bleeding, acute and chronic digestive tract bleeding, and symptoms due to deranged functions of involved organs.

Treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery or other targeted interventions to remove arteriovenous malformations in organs.

Chronic bleeding often has consequences of low hemoglobin and iron and so may require iron supplements and blood transfusions.

The disease is fairly common and occurs one in 5000 people (incidence of 0.02).

2 Symptoms

Telengectasias and arterio-venous malformations are the main symptoms of hereditary hemorrhagic telengectasia.

The sites commonly affected include:

  • nasopharynx,
  • CNS,
  • lung,
  • liver and spleen
  • as well as gastrointestinal tract,
  • conjunctiva,
  • urinary tract,
  • trunk,
  • arms
  • and fingers.

Commonest presenting symptom is recurrent epistaxis that is the most common morbidity caused by the disease. 90% of patients manifest by 40 years or later.

Clinically the diagnosis is on the basis of Curacao criteria

  • Epistaxis
  • Telangiectasias
  • Visceral lesions
  • Family history (a first-degree relative with HHT)

The disease is classified as definite if 3 or 4 criteria are present, probable or suspected if two criteria are present, unlikely if fewer than two.

Other symptoms may be

Pulmonary: affect 50% of patients. Dyspnea and exercise intolerance are often the presenting symptoms in such patients. Pulmonary AVMs may cause enough right-to-left shunt to result in hypoxemia, cyanosis, and secondary polycythemia. It also increases the risk of infection due to septic emboli formation in pulmonary vasculature. The disease can also manifest as pulmonary hypertension.

Telengiectasias: The mucous membranes are invariably involved. The tendency for telengiectasias usually runs in families and most of them manifest by 40 years of age.

Nuerological symptoms: Migraine headaches occur in 13-50% patients. Other presenting features include headache, seizures or focal nuerological deficits like paralysis. Stroke and brain abcess is more common in such patients as compared to normal patients. Spinal AVMs represent a rare manifestation that affects mainly children. Acute paraplegia may be the presenting feature in such sub-group of patients.

Gastrointestinal and hepatic symptoms: Recurrent and painless gastrointestinal bleeding occurs later in life of patients than epistaxis. Patients may report abdominal pain which may be due to thrombosis of abnormal vasculature. Due to liver involvement symptoms include jaundice, upper quadrant pain, high output failure, bleeding from oesophageal varices. Ocassionally, patients present with atypical cirhossis.

Other symptoms: Fatigue due to iron deficiency anemia, visual disturbance, bloody tears due to conjunctival hemorhages.

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3 Causes

Genetic mutations that involve signaling of TGF-β are the main causes of hereditary hemorrhagic telengectasia.

It is a genetically inherited disorder inherited in an autosomal dominant fashion.

At least four mutations have been described:

  • Mutations in ENG (coding endoglin),
  • in ALK-1 (encoding ALK-1),
  • of chromosome5 (5q31.1-32),
  • of SMAD4/MADH4 (encoding Smad4).

4 Making a Diagnosis

Your doctor may diagnose hereditary hemorrhagic telengectasia (HHT) on the basis of history, physical examination and laboratory investigations.

Your doctor may suggest you to undergo genetic testing for HHT which may establish the diagnosis.

The following imaging tests may be needed as a part of diagnostic work up:

  • Chest X-Ray: To asses size, shape and structure of lung and also to asses severity of lung disease.
  • Ultrasound:To detect abnormalities of liver.
  • MRI: To check vascular malformations of brain.
  • Bubble study or a contrast echocardiography: To screen for any abnormality in normal flow of blood caused by arteriovenous malformation in lung.
  • Computerised Tomography Scan: Is used to confirm the diagnosis and asses the need for surgery.
  • Colonoscopy and endoscopy: To look for polyps anywhere in people who have mutations in SMAD4.

5 Treatment

Treatment for hereditary hemorrhagic telengectasia (HHT) is medical and surgical. Treatment options are aimed at reducing the amount of blood loss and the sequelae of abnormal vasculature in multiple organs.

Indications for intervention vary according to site of involvement and presentation. When nonpharmacologic treatment is called for, it can often be accomplished via catheter-based therapies that render surgical intervention (eg, thoracotomy or craniotomy) unnecessary.

Skin lesions are treated by cautery, hypertonic saline soln, or by laser treatment. Severe cases are treated surgically with nasal septum skin transplants by using skin taken from the lower trunk.

Similarly, brisk hemorrhage of GI tract may call for endoscopy or surgical resection.

Pulmonary hemorrhage may be treated surgically by using silicone balloon tamponade or other means.

Severe liver disease may need liver transplantation.

For selected CNS lesions, neurosurgical resection may be indicated.

Embolization therapy and radiotherapy may be alternative options, depending on lesion morphology.

Some patients may require folate and iron supplements in case of chronic blood loss.

6 Prevention

Prevention of secondary complications:When pulmonary AVMs are present or suspected, antibiotic prophylaxis for dental and invasive procedures and a filter on intravenous lines to prevent air bubbles from being inadvertently infused is recommended.

Surveillance

Annual evaluations for anemia; evaluation for pulmonary AVMs by pulse oximetry every one to two years during the first decade of life and every five years by contrast echocardiogram thereafter.

Appearance of contrast on the left side of the heart after four to eight cardiac cycles, or in the presence of an intracardiac shunt, is evaluated further with high-resolution CT angiography of the chest.

While most cerebral AVMs are congenital lesions, reports of the development or evolution of cerebral AVMs in the first two decades of life exist; therefore, rescreening for cerebral AVMs through brain MRI is recommended after puberty if the initial brain MRI was done in childhood.

Periodic screening for gastrointestinal polyps and malignant change in persons with juvenile polyps is recommended.

Agents/circumstances to avoid

  • Vigorous nose blowing;
  • electric or chemical cautery for nosebleeds;
  • anticoagulant and anti-inflammatory agents (including aspirin) in individuals with significant nose or GI bleeding.

Genetic counseling

HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals have an affected parent. Each child of a proband and the sibs of most probands are at a 50% risk of inheriting the pathogenic variant. Prenatal testing is possible for pregnancies at increased risk if the pathogenic variant in the family is known.

7 Lifestyle and Coping

Lifestyle modifications are necessary in order to cope with hereditary hemorrhagic telengectasia.

The disease tends to run in families.

So affected individuals require genetic counseling for coping up with stress and planning their future.

Overall, life expectancy appears to be shortened by HHT, nevertheless, with appropriate screening and aggressive management, life expectancy for the majority of patients may approach that of the normal population.

8 Risks and Complications

There are complications associated with hereditary hemorrhagic telengectasia (HHT).

The complications of HHT can vary widely, even among people affected by HHT in the same family.

Complications and treatment of HHT depend on the parts of the body that are affected by this disorder.

Treatment may include controlling bleeding and anemia and preventing complications from abnormal artery-vein connections in the lungs and brain.

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