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may also lead to defective synthesis of von Willebrand Factor (VWF) and prolonged bleeding. There have been reports of families affected by both von Willebrand dis- ease (VWD) and HHT. This poses the question of a poten- tial relationship between the two diseases, which has been studied in published case reports. A potential type IIA VWD mutation (IIe865 to Thr) has been identified in affected families.36
While this is a simplified discussion of complex vascular biology, it illustrates why mutations in ENG, ACVRL1/ALK1, MADH4/SMAD4, and BMP9/GDF2 result in the HHT phenotype. A streamlined schematic summa- rizing the normal physiological signaling of the TGF-β pathway and the pathophysiology of HHT is shown in Figure 1.
Epidemiology and disease course
Hereditary hemorrhagic telangiectasia affects approxi- mately 1 in 5000 individuals in North America,37 but the highest prevalence is seen in the Afro-Caribbean regions of the Dutch Antilles and France.38 There is also variability regarding HHT subtype, with type 1 HHT being found more in North America and Europe and type 2 being more common in the Mediterranean and South America. However, these statistics may underestimate the actual dis- ease prevalence as the diagnosis is often missed and some patients may be asymptomatic. HHT exhibits incomplete penetrance and clinical manifestations can vary between patients, even within families with known mutations.
Patients may relate a history of epistaxis in childhood, often apparent during adolescence. Mild epistaxis or bleeding tendencies increase with age and telangiectasias may be seen after adolescence, often in adulthood.1 Clinical signs of bleeding become more apparent in adult- hood, often after the age of 40 years. Symptoms from ane- mia may be an initial complaint at presentation from gas- trointestinal bleeding, seen in approximately one-third of patients. Patients with mutations of ACVRL1 may present later in life, while those with MADH4 mutations may present earlier in childhood with juvenile colonic polyps and early onset colorectal cancer (at a mean age of 28 years).1,39
As a population, patients with HHT probably have a reduced life expectancy, but this is highly dependent on the severity of disease. Patients without internal organ manifestations (such as hepatic, cerebral or pulmonary AVMs) are expected to have a normal or near-normal lifes- pan, but approximately 10% of patients may die or become debilitated from vascular complications.40 In a large case-control study, 675 HHT patients were com- pared with age- and sex-matched healthy controls using a population-based UK primary care database. Patients with HHT were more likely to suffer from cerebral abscess, migraine, ischemic/embolic stroke, heart failure, colon cancer, and the numerous bleeding complications charac- teristic of the disease. The hazard ratio for death for patients with HHT compared with controls was 2.03 (CI: 1.59-2.60; P<0.0001).41 Life expectancy was seven years shorter in HHT patients in one study, with two mortality peaks, one under 50 years and one between 60-79 years of age.42 Finally, a population study in Denmark demonstrat- ed mortality rates double that of the general population in those under 60 years of age.43
Clinical manifestations
Patients with HHT vary in disease severity and bleeding complications. This variability is likely attributed to other genes, inflammation, and the environment that modify the primary genetic defect. Common AVM complications include epistaxis, GI bleeding, iron deficiency, iron deficien- cy anemia, ischemic and hemorrhagic stroke, brain abscess, high output heart failure, and liver failure.
It is suggested that certain mutated genes in HHT may be associated with specific clinical manifestations. ENG muta- tions may be associated with more pulmonary and brain AVMs; ACVRL1 with more liver AVMs, spinal AVMs, epis- taxis and pulmonary hypertension; and MADH4 with juve- nile colonic polyposis.44
Pulmonary AVMs
Pulmonary AVMs will develop in at least 50% of HHT patients and are more common in HHT1 than HHT2. Since approximately 70% of pulmonary AVMs are due to HHT, the diagnosis of HHT1 should be considered in all patients with pulmonary AVMs. Migraines are quite frequent in patients with pulmonary AVMs.45 Between 5 and 30% of patients may have pulmonary AVMs that may be asympto- matic or present as hemoptysis, dyspnea, hypoxemia or digital clubbing. Brain abscesses and stroke may occur fol- lowing “dirty” procedures (e.g. dental cleaning) if bacteria can bypass the pulmonary filtration system via right to left shunting from AVMs.46 Polycythemia may occur if there is significant AV shunting. The locus designated as HHT3 appears to predispose to pulmonary AVM formation.
LiverAVMs
Liver AVMs may be seen in up to 70% of patients with HHT. HHT2 appears to be associated with more liver AVMs. Although often asymptomatic, the shunting of blood through these AVMs in the liver can precipitate high- output heart failure, liver failure, or portal hypertension.
High-output heart failure
High-output heart failure can manifest due to large pul- monary AVMs and/or hepatic AVMs.47 High-output failure can be defined by: 1) symptoms of heart failure (such as shortness of breath, fatigue, and exercise intolerance); 2) cardiac output >8 L/min or cardiac index >3.9 L/min/m2; and 3) ejection fraction (EF) >50% and venous oxygen sat- uration >75%.48 Due to abnormal vascular flow through AVMs of the liver or lung, the vasculature may dilate because of increased high flow and/or decreased resistance. This causes the heart to compensate for the lower blood pressure with an increase in heart rate and output, leading to high-output failure. In these HHT patients, anemia may lead to an increased risk of heart failure due to the stress imposed from tachycardia and increased stroke volume.
Epistaxis
Epistaxis will manifest in approximately 50% of patients by the age of ten years. This increases with age such that 95% of all HHT patients eventually develop recurrent epis- taxis.49 This will become evident in adulthood with conse- quent iron deficiency anemia.
Gastrointestinal bleeding
When significant, gastrointestinal bleeding affects approximately 20% of patients. GI telangiectasias and
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haematologica | 2018; 103(9)