Hereditary Haemorrhagic Telangiectasia (HHT)

Genetics

Pathophysiology

Clinical Features

Diagnosis - Curaçao Criteria (3 of 4 = definite; 2 of 4 = possible)

1. Epistaxis - spontaneous, recurrent nosebleeds (most common sign; occurs in 93% of cases)
2. Telangiectases - multiple, at characteristic sites: lips, oral cavity, tongue, fingers, nose, nailbeds, palate, ears, soles, palms
3. Visceral lesions - GI bleeding; pulmonary, hepatic, cerebral, or spinal AVM
4. Family history - one affected first-degree relative

Clinical photo - Telangiectasias on the tongue:

Organ-by-Organ Involvement

Skin and Mucous Membranes

• Small, slightly elevated, bright red to violaceous tufts of dilated capillaries
• First appear at puberty on undersurface of tongue and floor of mouth
• Increase in number during middle age
• Blanch under pressure (distinguishing them from petechiae)

Epistaxis

• The most frequent and persistent sign
• Occurs in 93% of patients
• Worsening epistaxis can herald high-output cardiac failure from hepatic AVMs

Gastrointestinal

• GI bleeding is the presenting sign in up to 25% of patients
• 40-50% develop GI bleeding at some point during the disease
• Chronic iron-deficiency anaemia requiring iron and blood transfusions is characteristic

Pulmonary AVMs

• Can cause haemoptysis and hypoxaemia (right-to-left shunting)
• Major source of paradoxical embolism - predisposing to cerebral abscess and embolic stroke
• Screening recommended even in asymptomatic patients

Hepatic AVMs

• Hepatic artery-to-vein shunting can bypass parenchyma, causing high-output cardiac failure and liver failure
• Liver transplantation may be required in end-stage disease

CNS/Spinal

• Cerebral and spinal AVMs can cause haemorrhage or progressive focal deficits
• Cerebral abscess risk is elevated due to pulmonary AVM-mediated right-to-left shunts (bacteria bypass the pulmonary capillary filter)
• Retinal AV aneurysms occur rarely

Pregnancy

• Can exacerbate HHT; careful monitoring required

Screening

Management

Epistaxis

GI/Systemic Bleeding

• Iron supplementation and RBC transfusions for chronic anaemia
• Thalidomide and lenalidomide (blocks VEGF) - reduce GI bleeding and transfusion dependence
• Repeated Nd:YAG laser treatments to nasal and GI mucosa

AVMs

• Interventional radiology with selective embolization for pulmonary and CNS AVMs
• Liver transplantation for liver failure or high-output heart failure from hepatic AVMs

Anti-VEGF (Bevacizumab)

• IV bevacizumab has "dramatically improved some severely ill HHT patients," reducing hepatic AVM size and flow, reversing heart and liver failure, and reducing transfusion requirements
• Also used as submucosal injection and topical spray for epistaxis
• Efficacy remains debated for nasal disease specifically - Andrews' Diseases of the Skin, p. 980; Scott-Brown's ORL, Vol 1

Prophylaxis

• Antibiotic prophylaxis for dental and contaminated skin procedures is advocated by some, given the risk of cerebral abscess via pulmonary AVM right-to-left shunting

Differential Diagnosis

• CREST syndrome - mat telangiectases can closely simulate HHT but occur with other features of limited scleroderma (calcinosis, Raynaud's, oesophageal dysmotility, sclerodactyly)
• CM-AVM / CM-AVM2 (capillary malformation-AVM syndromes)
• Generalised essential telangiectasia
• Ataxia-telangiectasia

Key Points Summary

• Autosomal dominant; near-complete penetrance by age 50
• Core genes: ENG (HHT1) and ACVRL1 (HHT2) - together 85% of cases
• Diagnosis by Curaçao criteria (3/4 = definite)
• Epistaxis in 93%; GI bleeding in 40-50% over lifetime
• Screen all patients for pulmonary and CNS AVMs
• Cerebral abscess risk via pulmonary AVM right-to-left shunting is a life-threatening complication
• Bevacizumab (anti-VEGF) emerging as treatment for severe disease
• Large RCT evidence is lacking due to rarity of the condition

Hereditary Haemorrhagic Telangiectasia (HHT) - Rendu-Osler-Weber Disease

Classification in Pathology

"Telangiectasia is used to describe a permanent dilation of preexisting small vessels (capillaries, venules, and arterioles, usually in the skin or mucous membranes) that forms a discrete red lesion. These can be congenital or acquired and are not true neoplasms."

• Robbins, Cotran & Kumar Pathologic Basis of Disease

Definition

Genetics and Molecular Pathology

"At least five different genes, most of which modulate TGF-β signaling."

• Robbins, Cotran & Kumar, Chapter 14 (Bleeding Disorders)

"Patients with SMAD4 mutations often have both juvenile polyposis and hereditary hemorrhagic telangiectasia."

• Robbins, Cotran & Kumar, Chapter 17 (GI Pathology)

Pathophysiology

"The telangiectasias are malformations composed of dilated capillaries and veins that are present at birth. They are widely distributed over the skin and oral mucous membranes, as well as in the respiratory, gastrointestinal, and urinary tracts. The lesions can spontaneously rupture, causing serious epistaxis, gastrointestinal bleeding, or hematuria."

• Robbins & Kumar Basic Pathology, Chapter 8 (Vascular Ectasias)

Distribution of Lesions

• Skin: Face, hands, lips, fingertips, nailbeds, ears, palate
• Mucous membranes: Oral cavity (tongue, floor of mouth - first to appear at puberty), nasal mucosa
• Respiratory tract: Pulmonary AVMs
• GI tract: Stomach, small and large intestine
• Urinary tract: Bladder, kidney
• Liver: Hepatic AVMs
• CNS/Spinal cord: Cerebral and spinal AVMs

Clinical Features (Pathological Basis)

1. Epistaxis

• Most common and persistent sign (93% of patients)
• Due to telangiectasias of the nasal mucosa that rupture spontaneously
• Often the first presenting symptom in childhood/adolescence

2. GI Bleeding

• Second most common bleeding site
• Presenting sign in up to 25% of patients; 40-50% affected at some point in life
• Results in chronic iron-deficiency anaemia (microcytic, hypochromic)
• Requires iron supplementation and blood transfusions in severe cases

3. Hematuria

• From telangiectasias in urinary tract (less common)

4. Arteriovenous Malformations (AVMs)

• Pulmonary AVMs: Right-to-left shunting → hypoxaemia, polycythaemia, paradoxical embolism, cerebral abscess
• Hepatic AVMs: Hepatic artery-to-vein shunting → high-output cardiac failure, portal hypertension, liver failure
• Cerebral/Spinal AVMs: Haemorrhagic stroke, progressive focal deficits

Curaçao Diagnostic Criteria

Pathology Context: Where HHT Appears in Robbins

1. Vascular Pathology (Chapter 8/11)

• Listed under Vascular Ectasias, alongside nevus flammeus and spider telangiectasia
• Emphasises the structural basis of the lesion (dilated capillaries and veins, present at birth, TGF-β signalling defect in ECs)

2. Bleeding Disorders - Vessel Wall Abnormalities (Chapter 14)

• HHT is the most clinically significant cause of bleeding due to vessel wall abnormalities

"Among these conditions, serious bleeding is most often associated with hereditary hemorrhagic telangiectasia."

• Robbins, Cotran & Kumar, Chapter 14

• Context: Placed alongside Henoch-Schönlein purpura, scurvy, Ehlers-Danlos syndrome, and amyloidosis as vascular wall causes of bleeding

3. GI Pathology - Juvenile Polyposis (Chapter 17)

• SMAD4 mutations cause a combined phenotype of HHT + juvenile polyposis
• Juvenile polyposis with HHT carries 30-50% risk of colorectal adenocarcinoma by age 45

4. CNS Tumors / Soft Tissue (mentioned)

• AVMs associated with HHT mentioned among germline mutations predisposing to soft tissue tumours
• Cerebral AVMs in HHT can cause haemorrhagic stroke

Summary Box (Robbins-style)