Hereditary Hemorrhagic Telangiectasia

Clinical Manifestation

HHT patients present with complications resulting from their vascular malformations.  These can be bleeding from mucocutaneous telangiectasias, iron deficiency anemia due to chronic blood loss, or symptoms related to AVMs in visceral organs. There is considerable phenotypic heterogeneity in HHT and related individuals with the same familial HHT mutation demonstrate a wide spectrum of disease severity.

Recurrent epistaxis:

Epistaxis is the most common manifestation of HHT, with over 90% of patients developing epistaxis by age 40.³ In general, the frequency and severity of epistaxis tends to increase with age.¹³ Epistaxis can be influenced by a number of environmental factors, such as dry air (including using heating systems during colder months), environmental allergies (including occupational exposures), certain foods and supplements (generally preparations with antiplatelet activity), and comorbidities like poorly controlled hypertension. Injury and inflammation result in a proangiogenic milieu and can increase risk for the development of more telangiectasias and bleeding. Recurrent epistaxis has been shown to negatively impact quality of life in patients with HHT.^14,15

Gastrointestinal bleeding:

Gastrointestinal (GI) bleeding in HHT tends to occur after the age of 40 years, unless there is coexisting JPS (SMAD4 mutation patients), where it can occur earlier. The majority of patients with HHT will develop GI mucosal telangiectasias, although not all develop significant bleeding. There is a predilection for GI telangiectasias to develop in the small intestine,¹⁶ and bleeding is typically a chronic, intermittent, low-grade phenomenon with gradual development of iron deficiency and anemia over time.¹⁷

Telangiectasias:

Similar to epistaxis, mucocutaneous telangiectasias tend to develop with increasing age. Typically, these tend to develop over the face (cheeks), ear lobes, hands, and fingers (including nail beds). Telangiectasias can also develop over the buccal mucosa, gums and tongue. Cutaneous telangiectasias can occasionally bleed, but in general tend to be more of a cosmetic concern. Older patients can develop numerous facial telangiectasias resulting in affected individuals limiting social interactions.

Visceral organ AVMs:

Visceral organ AVMs tend to develop in the brain, lungs, and liver. Spinal AVMs are rare but reported.

Brain AVMs: Brain AVMs occur in 10-20% of HHT patients.¹⁸ These can be single or multiple. The likelihood of a diagnosis of HHT increases 50-fold in the presence of multiple brain AVMs.¹⁹ The most feared complication of brain AVMs is intracranial hemorrhage, with a bleeding risk of <2.5% per year.¹⁹ Interestingly, brain AVMs seem to develop in utero or in the first decade of life. While they may enlarge in size in adolescence and adulthood, patients do not develop new brain AVMs as adults. This is unique to brain AVMs as AVMs in other visceral organs can develop at any age.

Pulmonary AVMs: Pulmonary AVMs (PAVMs) develop in 30-50% of patients with HHT.^20,21 These can present with dyspnea or exercise intolerance (shunting and hypoxia), systemic infections/abscesses or stroke (paradoxical embolization across the AVM bypassing pulmonary capillaries), or hemoptysis (pulmonary hemorrhage). A higher prevalence of migraine is also reported in HHT patients with PAVMs.²²

Liver AVMs: Liver AVMs are relatively common with increasing age in HHT. They develop in 70% of patients with HHT. However, the vast majority of liver AVMs remain asymptomatic. A minority of patients develop high-output heart failure, portal hypertension or biliary necrosis depending on the circulatory beds connected by the AVMs.²³

Iron deficiency anemia:

Iron deficiency anemia (IDA) is the most common clinical manifestation in HHT patients after epistaxis and telangiectasias.²⁴ The prevalence of anemia in HHT patients is as high as 50%. IDA also tends to develop with increasing age and is the result of chronic, recurrent epistaxis and/or GI bleeding. It is important to note that patients can develop symptoms of fatigue, myalgias, decreased attention span, hair loss or restless leg syndrome with progressive iron deficiency even prior to the development of significant anemia.^25,26

Next