Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations

Abstract

Hereditary haemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome is an autosomal dominant disorder affecting 1 in 8000 individuals. The eponym recognises the 19th-century physicians William Osler, Henri Jules Louis Marie Rendu and Frederick Parkes Weber who each independently described the disease. It is characterised by epistaxis, telangiectasia and visceral arteriovenous malformations. Individuals with HHT have been found to have abnormal plasma concentrations of transforming growth factor beta and vascular endothelial growth factor secondary to mutations in ENG, ACVRL1 and MADH4. Pulmonary artery malformations (PAVMs) are abnormal communications between pulmonary arteries and veins and are found in up to 50% of individuals with HHT. The clinical features suggestive of PAVMs are stigmata of right to left shunting such as dyspnoea, hypoxaemia, cyanosis, cerebral embolism and unexplained haemoptysis or haemothorax. The authors present the case of a 33-year-old woman presenting with progressive dyspnoea during the COVID-19 pandemic. She had a typical presentation of HHT with recurrent epistaxis, telangiectasia and pulmonary arteriovenous malformations. Although rare, PAVM should be considered in individuals presenting to the emergency department with dyspnoea and hypoxaemia. Delayed diagnosis can result in fatal embolic and haemorrhagic complications.

Background

Hereditary haemorrhagic telangiectasia (HHT) is a syndrome with easily recognisable mucocutaneous arteriovenous malformations (AVMs) and covert visceral AVMs. On diagnosis, screening is recommended for pulmonary, cerebral, gastrointestinal and hepatic AVMs due to classically associated complications such as haemorrhage, cerebral abscess, high-output cardiac failure and iron deficiency anaemia. HHT is usually linked to the presence of a pathogenic mutation ACVRL1 (activin type II-like receptor kinase 1 gene encoding for the activin receptor-like kinase) or ENG (encoding for endoglin and mapped to locus 9q3). Pulmonary artery malformation (PAVM) is one of the classic manifestations of HHT and may be progressive in nature, although it can also present as an isolated finding. The most common symptoms are of dyspnoea, exercise intolerance migraine, stroke, transient ischaemic attack and lung haemorrhage. Catheter embolisation is regarded as the gold standard treatment for PAVM.

Case presentation

A 33-year-old female UK resident presented to the emergency department with a 3-month history of increased lethargy and shortness of breath on exertion during the COVID-19 pandemic. She had no history of coryzal symptoms, dysphagia, dysphonia, otalgia or weight loss. Her SpO₂ was recorded at 88% on air on exertion at home. There was no history of chest pain. Her medical history included migraine and epistaxis. She was recently diagnosed with hyperthyroidism secondary to Graves’ disease. Her medications included carbimazole 20mgs and sumatriptan 50mgs. She had no allergies. Her surgical history was unremarkable. Two years previously, her son, born by normal vaginal delivery, sustained an intracerebral haemorrhage aged 4 days thought likely secondary to a vascular malformation. She was a non-smoker, did not consume alcohol and was a keen runner. She was tachycardic, hypertensive and hypoxic with observations as follows: heart rate 125 beats per minute, BP 153/95 mm Hg, SpO₂ 88% on air, respiratory rate 22 and temperature 37°C. Neck examination confirmed a lump in the lower part of the right lobe of her thyroid gland and a Ultrasound Scan (USS) demonstrated a 17 mm simple cystic nodule in the lower pole of the right thyroid gland with a background of thyroiditis. Nasoendoscopy showed normal vocal cords. Oral mucosal examination demonstrated telangiectasia. Physical examination showed normal heart sounds. She was warm and well perfused with a capillary refill time of 2 s. Her jugular venous pulse was not raised. Her abdomen was soft and non-tender. Bowel sounds were audible on auscultation. Respiratory examination confirmed good air entry bilaterally. A bruit was audible at the lower left lung base. Skin examination was significant for macular, blanching telangiectasias on her fingers, lips and ears.

Investigations

Her 12 lead ECG showed sinus tachycardia (rate 120 beats per minute). Her chest radiograph showed a normal heart size with clear lungs and pleural spaces (figure 1). Her arterial blood gas on 1 L of oxygen showed the following: pH 7.47, pCO₂ 3.92, pO₂ 10.5, lactate 0.6, glucose 5.2 and HCO₃²⁻ 23.8. SARS-CoV-2 RNA was not detected. Laboratory investigations showed abnormal thyroid function tests, normal clotting and a mildly elevated alanine transaminase of 44 (normal <34) (table 1).

Figure 1.

Her chest radiograph was unremarkable.

Table 1.

Laboratory investigations

Haematology	Biochemistry
Haemoglobin 150 g/L	Sodium 141 mmol/L
White blood cell count 5.83×109/L	Potassium 5.0 mmol/L
Platelet count 225	Urea 6.4 mmol/L
Mean cell volume 84 fL	Creatinine 52
Haematocrit 0.453	Albumin 41
Mean cell haemoglobin 27.8 pg	Alkaline phosphatase 94
Neutrophil count 3.71	Alanine transaminase 44
Monocyte count 0.80
Eosinophil count 0.17	Calcium 2.32
Basophil count 0.02	Calcium adjusted 2.45
Clotting	C reactive protein 3 mg/L
Prothrombin time 13.8
APTT 28.6	D-dimer 446
Thyroid function tests
TSH <0.01	TSH receptor Ab 28
Free T4 73
Free T3 20.6

APTT, Activated Partial Thromboplastin Time; TSH, Thyroid Stimulating Hormone.

A CT thorax with contrast was performed. Post-contrast imaging obtained through the chest showed an AVM in the left costophrenic recess with a large supplying artery and a markedly enlarging draining vein (figure 2). A further smaller AVM was identified superiorly within the right middle lobe (figure 3). There was a tiny nodular density in the periphery of the right lower lobe reflecting a further tiny AVM. There was no evidence of confluent consolidation or a pleural effusion. Minor atelectasis was seen in the left lower lobe. There was mild distension of the pulmonary trunk, the heart size was normal. The thoracic aorta and the arch vessels were normal. A well-defined lobulated soft tissue mass in the anterior mediastinum measuring 46 mm×32 mm extending 113 mm cranially to the sternal notch and adjacent to the lower margin of the thyroid gland was noted. The lesion was likely to represent thymic hyperplasia which is unusual in this age group; however, this may be secondary to chronic hypoxia (figure 4). There was a cyst arising from the lower pole of the right lobe of thyroid with mild thickening of the thyroid isthmus. No significant supraclavicular adenopathy was noted. Her transthoracic echocardiogram showed no cardiac abnormality and no evidence of raised pulmonary pressure (figure 5). Her ejection fraction was 63%.

Figure 2.

A post-contrast CT thorax obtained through the chest showed an arteriovenous malformation in the left costophrenic recess with a large supplying artery and a markedly enlarging draining vein.

Figure 3.

A further smaller arteriovenous malformation was identified superiorly within the right middle lobe.

Figure 4.

A well-defined lobulated soft tissue mass in the anterior mediastinum measuring 46 mm in maximal transverse diameter × 3 mm in AP diameter and extending 113 mm in a craniocaudal extent was noted. This extended cranially to the sternal notch and appeared to be adjacent to the lower margin of the thyroid gland.

Figure 5.

Her transthoracic echocardiogram showed no cardiac abnormality, a non-dilated and normally functioning right ventricle, no evidence for raised pulmonary pressure, but a dilated mean pulmonary artery of 37 mm (mean normal value by echo ~27 mm).

Initial diagnosis

Due to the presence of an audible bruit, history of epistaxis, telangiectasia, a first degree relative with a vascular malformation and her CT findings, the clinical suspicion was of HHT with a PAVM. Genetic testing confirmed the diagnosis with the identification of ACVRL1.

Treatment

She commenced treatment with carbimazole 40 mg once daily. Her thyroid function tests improved (TSH <0.01 mU/L, FT4 22.2 pmol/L and FT3 12.2 pmol/L). Her carbimazole dose was titrated accordingly and reduced to 30 mgs once daily. Due to the COVID-19 pandemic, she remains under review in the virtual endocrinology clinic.

Outcome and follow-up

She was referred to a tertiary centre for further evaluation of her PAVMs. Transcatheter embolisation of her PAVM is awaited. She remains under review in the endocrinology clinic.

Discussion

HHT, otherwise known as Osler-Weber-Rendu syndrome, is an autosomal dominant inherited condition with a prevalence of 1:8000. It is characterised by recurrent epistaxis, cutaneous telangiectasia and AVMs that affect many organs including the lungs, gastrointestinal tract, liver and central nervous system.

Approximately 50% develop pulmonary AVMs. The first clinical manifestations of HHT were described in 1865 by Benjamin Guy Babington and John Wickham Legg in 1876.¹ In 1886, Henri Jules Louis Marie Rendu distinguished the disease from haemophilia. It was further described by William Osler in 1901 and 1907.² Studies have shown that 4.3%–7.6% of HHT admissions annually are related to a PAVM diagnosis and 1%–3% require pulmonary artery arteriography.³ A recent retrospective single-centre study has shown that pathogenic variants in ENG, ACVRL1, SMAD4 and GDF2 results in gene-specific HHT clinical presentation.⁴ Penetrance is age-related and is nearly complete by age 40. Although the AVM in HHT is inherited and should be present at birth, they seldom manifest clinically until adult life, after the vessels have been subjected to pressure over several decades. The frequency of pulmonary AVMs is higher in the ENG group.⁴ A clinical diagnosis of HHT can be made in the presence of three out of four Curacao criteria, which include the presence of multiple mucocutaneous telangiectasis, spontaneous and recurrent epistaxis, visceral involvement (pulmonary, cerebral, liver, spine, gastrointestinal) and a first-degree family history of HHT.⁵ Superficial telangiectases attributable to HHT are the most common and frequently the only physical finding in patients with PAVM. These ruby-coloured lesions are slightly rounded, 1–3 mm in diameter, sharply demarcated from the surrounding skin with few dendritic projections and blanch partially with pressure. In HHT, low haemoglobin and low serum haptoglobin are often attributed to gastrointestinal bleeding and intravascular haemolysis contributing to severe anaemia.⁶ Polycythaemia can occur if there is significant AV shunting.

Pulmonary AVMs, first described at autopsy in 1897 and during life in 1939, are abnormal direct communications between pulmonary arteries and pulmonary veins without interposition of a capillary bed.^{7 8} Abnormal communications between blood vessels of the lung may occur in acquired conditions. Right-to-left shunting as a result of communications between pulmonary arteries and pulmonary veins has been reported in hepatic cirrhosis and less commonly in schistosomiasis, mitral stenosis, trauma, actinomycosis, Fanconi’s anaemia and metastatic thyroid cancer. Communications between bronchial arteries and pulmonary arteries, causing left-to-right shunt, can develop in chronic inflammatory conditions such as bronchiectasis.⁹ The exact pathogenesis of PAVM remains to be fully elucidated. It has been hypothesised that the cause is a defect in terminal arterial loops which allows dilatation of thin-walled capillary sacs or the result of incomplete resorption of the vascular septae that separate the arterial and venous plexuses which normally anastomose during fetal development.¹⁰ Individual PAVMs are typically 1–5 cm in size, although they can be >10 cm and can spread over the surface of the lung like a Medusa’s head.¹¹ In children and young adults with HHT, Grade 4 PAVMs (ground glass opacity or nodule with two or more vascular networks) are most common.¹² PAVMs allow a proportion of the right ventricular stroke volume to bypass gas exchange, filtration and other functions of the pulmonary capillary bed. Patients may be asymptomatic or present with bloody sputum, dyspnoea, cyanosis or platypnea (improvement in breathing on reclining). A murmur or bruit over the site of the PAVM, as in our case, is audible in 46% of patients mostly during inspiration. In HHT, hepatic AVM is considered the most prevalent visceral AVM, although >90% can be clinically silent and these patients are usually carriers of the ACVRL mutations.¹³

Severe complications can occur including epistaxis, haemothorax, haemoptysis and severe hypoxaemia due to right-to-left shunting. Decompensated heart failure, dyspnoea related to heart failure and hepatobiliary necrosis are complications related to hepatic AVMs. Postpartum complications can occur due to paradoxical cerebral embolism secondary to cardiac shunts caused by PAVM, in addition to posterior reversible encephalopathy syndrome and an eclamptic attack. Neurological complications including an intracranial haemorrhage, transient ischaemic attack, cerebral stroke and abscess due to the right-to-left shunting that facilitates the passage of septic emboli into the cerebral circulation can occur.

The classic chest radiograph appearance of a PAVM is that of a round or oval mass of uniform density 1–5 cm in diameter, more commonly in the lower lobes. The PAVM may be obscured by haemorrhage into contiguous parenchyma or by atelectasis resulting from bronchial compression, and only a vague increase in the pulmonary markings at the bases may be observed. Individual PAVM will often show feeding vessels on chest radiography, with the artery radiating from the hilus and the vein deviating towards the left atrium. The pulmonary artery pressure is normal or low in nearly all patients. Contrast echocardiography is an excellent tool for evaluation of cardiac and intrapulmonary shunts and is able to identify right-to-left shunts even when they are not suggested by gas exchange data.

All patients over 16 years with known or suspected HHT should be offered screening for HHT.¹⁴ For an individual with PAVMs due to HHT, a first-degree family member has a one in four risk of PAVMs. Adult patients who have had a negative screen for pulmonary AVMs are at low risk of developing pulmonary AVMs later in life.¹⁵ Children who had a negative PAVM screen require a repeat screening in adult life. Close monitoring with CT every 3–5 years is recommended in patients with HHT and inconclusive screening results to detect progression to PAVMs amenable to vaso-occlusion and to prevent neurological complications.

Treatment decisions should be made in a multidisciplinary context. Between 1942 and 1977, surgery was the only method of treatment with ligation, local excision, segmentectomy, lobectomy or pneumonectomy performed in most cases. Given the rarity of this disease, only a few studies have suggested treatment for HHT, including Vascular Endothelial Growth Factor (VEGF) inhibitor bevacizumab, a recombinant humanised monoclonal antibody that blocks angiogenesis via VEGF inhibition.¹⁵ It has been suggested that tacrolimus, a calcineurin inhibitor used principally as an immunosuppressive therapy, may have a therapeutic role. The treatment of choice is transcatheter embolisation, even for asymptomatic patients, with the most common embolic devices being coils or Amplatzer plugs to occlude the malformation. The first successful case of embolotherapy of PAVM was reported by Porstmann in 1977 using hand-made steel coils.¹⁶ PAVM treatment reduces the risk from paradoxical emboli and improves oxygenation, as well as symptoms exacerbated by right-to-left shunting. If PAVM closure is achieved, gas exchange improves immediately post embolisation, while haematological and haemodynamic compensations are lost over weeks to months. Regression of most PAVM sacs, dilated feeding arteries and draining veins occurs over 3–6 months.¹⁷ Recurrent PAVMs are challenging to treat with high rates of recurrence following repeat embolisation. Distal embolisation technique is more likely to produce a durable occlusion than proximal embolisation.¹⁸ Multiple pulmonary abscesses as a late complication after PAVMs can occur.¹⁹ Persistence of PAVMs after embolisation occurs for undefined reasons but may include inflammation related to smoking in dysregulated angiogenesis. New onset haemoptysis in a previously treated patient should raise the possibility of haemorrhage arising from PAVM sacs persisting post embolisation with an acquired systemic arterial collateral blood supply.²⁰ The most common cause for PAVM recanalisation is blood flow through a previously placed coil nest, presumed to be caused by the fact that the pulmonary artery can stretch more than the systemic artery. Other causes include pulmonary artery-to-pulmonary artery reperfusion, in which the embolised feeding artery remains occluded but small feeders develop from adjacent normal pulmonary arteries and incomplete initial treatment in which previously untreated feeders of a complex PAVM are present.²¹

Between July 2016 and September 2018, NHS Genomic Medicine Centres recruited families with specified rare diseases to the 100 000 Genomes Project for whole genome sequencing and linkage to phenotypic information from NHS Health Records. Six respiratory diseases including HHT and PAVM were nominated.²² Cannavicci’s research has successfully identified mRNA dysregulation and elevated IGF1 mRNA levels in patient-derived peripheral blood mononuclear cells. This novel discovery represents a potential pathogenic mechanism that could be targeted to alleviate clinical manifestations of HHT.²³

Learning points.

• Symptoms in early life may vary from being totally absent to severe with pulmonary artery malformations (PAVMs) resulting in hypoxia, cyanosis, congestive heart failure, fulminant respiratory failure, cerebral embolism and abscess formation due to shunting. They are mostly associated with hereditary haemorrhagic telangiectasia (HHT) but acquired PAVMs secondary to infection and trauma can occur. Superficial telangiectasis attributable to HHT are the most common physical finding in patients with PAVM.

• The most common complaint in symptomatic patients is epistaxis, which is caused by bleeding from mucosal telangiectasis, is characteristically spontaneous or precipitated by minor trauma.

• PAVMs may rupture causing life-threatening complications such as haemoptysis or haemothorax. Haemothorax may result from rupture of a subpleural PAVM, while haemoptysis may result from a ruptured PAVM or endobronchial telangiectasia.

• CT angiography is chosen as a non-invasive technique for its detection. Selective embolisation is the first-line treatment procedure. The success of embolisation can be confirmed when the sac disappears or becomes scarred.