Continuing Education Activity

Hereditary hemorrhagic telangiectasias (HHT) is an autosomal dominant bleeding disorder due to the presence of malformed vessels. The condition manifests as telangiectasias affecting the skin and mucosa and arteriovenous malformations involving organs like the lung, brain, and liver. This activity reviews the pathophysiology of the disease and emphasizes the importance of an interprofessional team’s approach to the evaluation and treatment of patients with this condition.

Objectives:

• Summarize the pertinent history and physical exam findings associated with HHT and additional tests to diagnose the condition.

• Review the pathophysiology of HHT and its clinical manifestations.

• Explain medical treatment options available for HHT.

• Describe the procedures or surgical interventions for HHT and how to select the best treatment based on patient presentation.

Introduction

Hereditary hemorrhagic telangiectasia (HHT), formerly Osler-Weber-Rendu, is an inherited (autosomal dominant) disease that results in malformed blood vessels (see Image. Telangiectasia on the Tongue). The disease is named after the physicians who first independently described the condition: Henri Jules Louis Marie Rendu in 1896, William Osler in 1901, and Frederick Parkes Weber in 1907.[1] 

The malformations typically manifest as mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs).[2] These vascular malformations are responsible for much of the clinical bleeding associated with this disease, ranging from mild epistaxis to life-threatening intracranial bleeds.[3][4][5] Some patients with HHT develop pulmonary hypertension, prothrombotic state, or immune dysfunction.[6]

The earliest clinical sign of HHT, often occurring by the second decade of life, is recurrent epistaxis. Telangiectasias, which are dilated blood vessels, are frequently present on the skin and buccal mucosa in the third decade of life. The number of telangiectasias increase with age, which is regularly accompanied by increased frequency of epistaxis or gastrointestinal (GI) bleeds, leading to anemia, poorer quality of life, and increased healthcare resource utilization, including iron or blood transfusions and hospitalizations.[7]

Etiology

Genes are comprised of DNA, which encodes for distinct proteins that perform a specific function in the body. Through transcription, the DNA is converted into messenger RNA (mRNA) and then translated into a protein. HHT is an autosomal dominant disorder that can affect blood vessels within multiple organ systems. The condition is suspected to be haploinsufficiency, where one functional gene copy cannot produce the required protein to preserve function.[2] 

In 97% of patients with a definite clinical HHT diagnosis, a causative mutation is identified in one of three genes, described below.[8] These mutations disrupt signaling by transforming growth factor-beta (TGF-B), which is essential for maintaining vascular integrity.[9][10][11]

HHT Type I (HHT1)

HHT1 stems from mutations in the gene ENG, which codes for endoglin on chromosome 9.[12] Endoglin is a membrane glycoprotein that is part of the tumor growth factor-beta (TGF-B) receptor complex needed for vascular integrity.

HHT Type 2 (HHT2)

HHT2 results from mutations in Activin A receptor-like type I (ACVRL1), which codes for the protein activin receptor-like kinase 1 (ALK1) on chromosome 12.[13] ALK1 is a type 1 cell-surface receptor for the TGF-B superfamily and is found on the surface of cells, particularly on the lining of developing arteries.[14]

HHT Associated with Juvenile Polyposis (JPHT or JP-HHT)

JPHT is due to a mutation in the gene Mothers Against Decapentaplegic homolog 4 (MADH4) that codes for the transcription factor SMAD4, a critical downstream effector of TGF-B signaling.[15] The mutations in JPHT are located on the last four exons of Smad4 and include several mutation types, including nonsense, missense, frameshift, and de novo.[6]

The distribution in gene mutations among HHT patients is predominantly ENG (61%), followed by ACVRL1 (37%), and then MADH4 (2%). Additionally, more than 600 mutations, including deletions, missense, nonsense, and insertions, have been identified in either ENG or ACVR genes.

Epidemiology

HHT affects 1 in 5,000-8,000 individuals and can affect both genders and people of all races.[2][5][6][7] Some studies have noted a higher incidence in women, although this gender difference may be attributed to access to healthcare resources.[16][17]

Pathophysiology

Pathogenesis of HHT is primarily due to the gene mutations (endoglin, ACVRL1, and SMAD4) that affect the endothelial cell receptors of the TGF-B superfamily. A mutation in these receptors prevents downstream signaling and disrupts angiogenesis, promoting disorganized cytoskeleton and dysfunctional remodeling of the vascular endothelium. As a result, these vessels exhibit a loss of elasticity and remain chronically dilated.[18]

The loss of vascular integrity, combined with constant pressure, results in the formation of telangiectasias (dilated microvessels) and large AVMs.[19][9] Due to the decreased elasticity of the vessel walls and dilation of the vascular lumen, telangiectasias are fragile and more prone to hemorrhage. AVMs can form in the brain, lungs, GI tract, spine, or liver.[19] 

Up to 10% of HHT patients have cerebral AVMs, 15 to 45% develop pulmonary AVMs, and 75% have hepatic AVMs. Rupture of these AVMs can result in severe complications, including internal hemorrhage, embolic or hemorrhagic stroke, seizures, migraines, or brain abscesses.[17] Untreated pulmonary and hepatic AVMs can lead to arteriovenous shunting and pulmonary hypertension.[6]

There are phenotypic variations between HHT1 and HHT2. HHT1 patients develop epistaxis earlier in life and have pulmonary AVMs, while HHT2 patients are more likely to develop hepatic AVMs.[20]

Histopathology

Normally, arteries and veins are connected by an intermediary capillary system. AVMs and telangiectasias lack this intermediary, with a direct connection between the artery and the vein. Telangiectasias occur on mucocutaneous surfaces, while AVMs are found within internal organs (see Image. Ocular Telangiectasia). Histological evaluation of AVMs shows irregular endothelium, increased collagen and actin deposition in the basement membrane, and a disorganized basement membrane.[21]

History and Physical

Although autosomal dominant, the clinical manifestations of HHT are variable, even within families.[6] The classic triad consists of epistaxis, telangiectasias, and positive family history of similarly affected individuals.

Epistaxis

The earliest clinical manifestation and primary complaint in up to 96% of patients are spontaneous, recurrent epistaxis, stemming from nasal mucosal telangiectasias. Epistaxis can occur as early as childhood and increases in prevalence with age, potentially resulting in anemia and the need for blood and/or iron transfusions. The average age of epistaxis onset is 12 years, with almost 100% of HHT patients affected by 40 years and an average number of 18 bleeds per month.[22][23]

Evaluation of epistaxis should involve anterior rhinoscopy of the nasal cavity. If resources are available, nasal endoscopy and/or upper airway endoscopy with a rigid or flexible fiberoptic scope can be done to evaluate for the presence of telangiectasias in the nasal or oral mucosa (see Image. Telangiectasia in Nasal Cavity). However, great care needs to be taken to avoid unnecessary bleeding.

Mucocutaneous Telangiectasias

Telangiectasias of the skin and oral mucosa appear around the 3rd decade and increase in number and frequency with age.[6] Recurrent GI bleeds manifest later in 15-20% of HHT patients.[7] Patients should be queried about bleeding frequency and severity. On physical exam, HHT patients have telangiectasias involving the nasal mucosa, oral cavity including hard palate, tongue, and lips, as well as cutaneous lesions on the fingers and nose (see Images. HHT Telangiectasias on Thumb and Lip Telangiectasia).[9]

Cutaneous Telangiectasias on the Fingers

Visceral Arteriovenous Malformations (AVM)

Patients may also develop AVMs of the lungs, GI tract, brain, liver, or spine. AVM-related symptoms and complications should be assessed, including a history of stroke, heart failure, venous thromboembolism, iron deficiency, brain abscesses, arteriovenous shunting, liver disease, migraines, and pulmonary hypertension.[19]

Cerebral and pulmonary AVMs typically form perinatally and pre-puberty, respectively.[24] In addition, because patients with the JPHT form are at higher odds for developing colon cancer, patients should be queried for signs or symptoms of colorectal cancer such as weight loss, change in bowel habits, and history of colorectal cancer among affected family members.

On exam, patients may present with hepatomegaly, or hepatic bruits due to the left-to-right shunting of blood in hepatic AVMs.[25] Additionally, patients may exhibit pallor due to chronic anemia.

Family History

In patients with a positive family history of HHT, the presence of a visceral AVM essentially confirms the diagnosis since AVMs are rare in the general population. For unaffected patients with a parent with HHT, the disease cannot be ruled out due to variable age-related onset of signs and symptoms. European studies on HHT patients estimate the probability of clinical HHT in patients with an affected family member to range from 0.5, 0.22, and 0.01 at 0-, 16-, and 60 years.[7][26]

Classification Criteria

The diagnosis of HHT has relied on Curaçao Criteria, which encompasses the classic features of the disease: 1) spontaneous, recurrent epistaxis, 2) positive family history, 3) cutaneous or mucosal telangiectasias, and 4) visceral lesions. A definitive diagnosis is made if patients have 3 of the 4 criteria, and a possible or suspected diagnosis is made if patients meet 2 of the 4 criteria.[5] Of note, the criteria have a poor negative predictive value in children under the age of 16 years.[27]

Evaluation

Genetic Testing

Genetic mutation testing should be done to confirm a diagnosis of HHT, including patients who meet 1-2 of the Curaçao criteria or young children with affected parents who are yet to develop the clinical manifestations.[19] Initial genetic testing should screen for the three most prevalent mutations, ENG, ACVRL1, and SMAD4. Testing should also be extended to family members. It is important to note that genetic mutations are not identified in up to 10 to 15% of HHT families, and a negative genetic test does not exclude the diagnosis of HHT.

Once the diagnosis is confirmed, additional tests can be done to evaluate for other HHT manifestations. Screening should be done, regardless of a patient’s clinical symptoms, due to the danger of undiagnosed silent AVMs. 

Ancillary Tests for Visceral AVMs

Pulmonary AVMs are often silent but can lead to strokes, massive hemoptysis, spontaneous hemothorax, transient ischemic attacks, and brain abscesses.[22] Sensitive screening tests to detect pulmonary AVMs include thoracic CT scan and transthoracic contrast/bubble echocardiography; both modalities can also detect pulmonary hypertension. Most screening protocols use contrast echocardiography as a first-line test, followed by a thoracic CT to determine the anatomic location and if embolization is a viable option. Chest x-rays, right-to-left shunt measurements, and blood oxygen measurements are less sensitive to identifying the presence of pulmonary AVMs.

Multiple cerebral AVMs are predictive of HHT.[28] The role of screening remains controversial due to the overall low risk, albeit significant morbidity or mortality, of hemorrhage. Additionally, the risks associated with treating asymptomatic cerebral AVMs potentially outweigh the benefits. An MRI brain with and without contrast is initially recommended for patients with cerebral symptoms, who have a known unstable cerebral aneurysm, or a family member who has had a cerebral hemorrhage since familial aneurysms have a higher risk of hemorrhage.[29] The gold standard for diagnosing and treating cerebral AVMs is a diagnostic angiography, which carries a 0.5% risk of stroke.[25]

Routine gastrointestinal (GI) endoscopy is not typically performed. However, patients with anemia disproportionate to the severity of epistaxis or with a history of GI bleeding should undergo an esophagogastroduodenoscopy (EGD) to detect and treat GI AVMs.[9][22] If EGD is inconclusive, capsule endoscopy can be considered. Additionally, patients with the JPHT form of HHT should have a screening colonoscopy starting at the age of 15 due to a higher risk of colon cancer. This should be repeated every three years if no colon polyps are found. If polyps are detected, the patient should undergo yearly EGD and colonoscopy.[22] 

Screening for asymptomatic hepatic AVMs with doppler ultrasonography is recommended because it is non-invasive and can improve patient management and outcomes. While doppler ultrasonography is ideal due to its accuracy, cost, safety, and tolerability depending on resources available and operator expertise, patients can be screened by alternate means, such as multiphase contrast CT or MRI.[19][6]

Laboratory Evaluation

Laboratory testing should be done before all surgical interventions and includes a complete blood count and a type and screen or type and crossmatch.[9] Furthermore, all adults, regardless of symptoms, and children with recurrent bleeding should have annual complete blood count and ferritin levels measured to screen for iron deficiency anemia. If the patient is anemic but ferritin is normal, further workup with serum iron, transferrin saturation, and total iron-binding capacity should be performed.[19][22] HHT patients with severe epistaxis demonstrate microcytic iron deficiency anemia with low ferritin and elevated transferrin.[9]  

Pregnancy

Pregnant women with HHT should have access to a multidisciplinary maternal-fetal team with knowledge on HHT, and pre-conception and prenatal diagnostic options should be discussed. Asymptomatic pregnant women should have an agitated saline transthoracic contrast echocardiography (TTCE) or a diagnostic low-dose chest CT without contrast for pulmonary AVMs. Any intervention should be delayed until the 2nd trimester.[22] 

Spinal AVMs can be detected with a spinal MRI and can be considered in pregnant women, particularly if epidural anesthesia is considered.[6] However, an expert consensus panel recommended against withholding an epidural, as risks of complications are unsubstantiated. Pregnant women with symptomatic cerebral AVMs or previous cerebral hemorrhage should have an unenhanced MRI in the second trimester. For asymptomatic cerebral AVMs, vaginal delivery may be attempted. However, for HHT patients with symptomatic cerebral AVMs or prior hemorrhage, a cesarean section should be considered to avoid the strain associated with delivering vaginally.[22]

Treatment / Management

Treatment options are tailored to the patient, and the best approach is based on local versus systemic measures. Due to the few randomized trials, there are no standard therapies for HHT. Management of HHT focuses on supportive care, preventing complications, and reducing symptom severity.

Epistaxis

Epistaxis prevention is the primary goal for HHT-related nosebleeds. Preventative measures include the use of topical moisturizers and emollients, nasal hygiene with humidifiers and nasal saline irrigations, and avoidance of triggers and blood thinners.[30][19] Conservative management of ongoing epistaxis includes topical decongestant spray, manual pressure, absorbable nasal packing, and chemical cauterization with silver nitrate.[9] Non-dissolvable nasal packing should be avoided due to the risk of increased mucosal trauma with insertion and removal of the packing. Epistaxis refractory to conservative measures may require surgical or endovascular interventions.[19]

Other medical interventions targeting the molecular biology of the disease have been used – many of which have gained and lost favor. The goals of these medical treatments are to reduce the frequency, volume, and severity of nosebleeds and improve quality of life. These topical and oral agents include estrogen agents (tamoxifen, raloxifene, and estriol ointment), tranexamic acid, thalidomide, beta-blockers (timolol or propranolol), and vascular endothelial growth factor (VEGF) inhibitors (bevacizumab).[9][31] 

Oral tranexamic acid is a possible option for treating HHT-epistaxis refractory to moisturizing topical therapies.[32] Two randomized control trials evaluating oral tranexamic acid for HHT-related epistaxis demonstrated a 17.3% reduction in epistaxis duration and a 54% reduction in epistaxis intensity.[33][34]

Surgical interventions focused on prevention and reducing severity include electrosurgical plasma coagulation, potassium titanyl phosphate (KTP) laser photocoagulation, and sclerotherapy with sodium tetradecyl sulfate (STS).[35] Laser photocoagulation improves the quality of life outcomes and decreases the frequency and severity of epistaxis. Other surgical interventions for moderate to severe epistaxis include septodermoplasty and Young’s procedure. Septodermoplasty involves removing the sinonasal mucosal and replacement with a split-thickness skin graft.[36] 

After the surgery, there is a reduction in epistaxis for at least two years, though the problem typically recurs with time as telangiectasias affect the graft. This procedure has lost favor among many. Young’s procedure, which is technically reversible, involves the closure of one or both nostrils using mucocutaneous flaps, resulting in complete obstruction of airflow through the nose and resolution of epistaxis.[37] After Young’s procedure, patients suffer hyposmia and hypogeusia but also have complete cessation of epistaxis. This procedure is reserved for severe, life-threatening epistaxis and is relatively uncommon.

Anemia and Anticoagulation

All patients with iron deficiency and anemia require iron replacement, either orally or intravenously, if the oral form is not absorbed or well-tolerated. Oral replacement starts with 35 to 65 mg of elemental iron daily, taken either 2 hours prior or 1 hour after meals. For refractory or severe anemia, IV iron infusions may be required regularly, starting at 1 gm in a single dose or divided infusions.[38] Blood transfusions should be considered in the following situations: hemodynamic shock, presence of comorbidities requiring higher hemoglobin baseline prior to surgery or pregnancy, or inadequate hemoglobin levels despite iron transfusions.

Anticoagulation is permissible in HHT patients.[39] Vitamin K antagonists and unfractionated and low-molecular-weight heparins are preferred and better than direct-acting oral anticoagulants (DOACs). Currently, there is more literature regarding tolerance with heparin and warfarin in HHT patients. In fact, warfarin is the oral anticoagulant of choice because of its tolerance and the existence of a reversal agent. Finally, a small retrospective study evaluating DOAC showed an increase in HHT-related epistaxis while on DOACs.[40] If dual therapy is required, the duration of treatment should be minimized, and patients closely observed.

GI Bleeding

Patients with mild to moderate HHT-related GI bleeding can be managed with iron replacement. For severe cases, hemoglobin can be managed with scheduled iron replacement and transfusions. For patients with moderate to severe GI bleeding refractory to iron replacement and transfusions, there is moderate evidence for intravenous bevacizumab or other systemic antiangiogenic therapy and inadequate evidence for oral antifibrinolytics. Endoscopic argon plasma coagulation is an option to address bleeding and non-bleeding lesions during upper GI endoscopy; however, the evidence for this is low.[22]

Pulmonary AVMs (PAVMs)

Detection and treatment of asymptomatic PAVM are recommended due to associated neurological risks, including brain abscesses and paradoxical embolic strokes. The mainstay treatment of PAVMs is transcatheter embolization with embolic material such as metallic coils and Amplatzer vascular plugs.[25][22][41] 

A CT chest is recommended 3 to 6 months after the procedure to ensure recanalization of the occluded feeding artery did not occur. Surgery is reserved only for life-threatening hemorrhage. Similarly, lung transplantation is limited to patients with diffuse bilateral disease refractory to other treatment modalities.

There is an association between oral microorganisms and PAVM-associated brain abscesses.[42] The pulmonary capillary bed filters small thrombi and bacteria that enter the bloodstream. Since the capillary bed is bypassed in PAVMs, a direct right to left shunt effectively forms, allowing paradoxical emboli to pass and cause brain abscesses or stroke.[43] Thus, antibiotic prophylaxis is recommended for any procedure that carries a risk of bacteremia, particularly dental procedures. Finally, patients with PAVMs should be followed long-term to detect the growth of untreated PAVMs and reperfusion of treated PAVMS.

Hepatic AVMs (HAVMs)

Management of HAVMs is based on the symptoms and type of complications. HHT patients with HAVMs may have high-output cardiac failure, portal hypertension, or cirrhosis, which are managed medically. High-output cardiac failure is treated with blood transfusions for anemia, salt and fluid restriction, beta-blockers, and diuretics. Intravenous bevacizumab can be considered for patients with high-output cardiac failure who fail initial management. Portal hypertension and cirrhosis are treated with salt and fluid restriction, diuretics, and paracentesis. Liver transplantation is reserved for those with symptomatic HAVMs who are refractory to medical management.[44] Finally, hepatic artery embolization should be avoided since the procedure is only temporizing and carries high morbidity and mortality.

Cerebral AVMs (CAVMs)

HHT-related CAVMs are low-grade, usually small, and cortically located with superficial venous drainage. Patients who are symptomatic from CAVMs should be referred to a center with neurovascular expertise. The natural history of CAVMs associated with HHT is slightly more favorable than sporadic AVMs, with a yearly rupture rate of 1.3% vs. 2.2%.[45][46] 

As such, conservative management should be considered for CAVMs in HHT patients. Furthermore, although there are advances in interventional therapies for CAVMs, these benefits appear to still be outweighed by the risks. The ARUBA trial evaluated interventional versus medical therapy for 223 non-HHT patients with CAVMs and found the risk of stroke or death to be three times higher (30.7% vs. 10.1%) in the interventional arm.[46]

For HHT patients with symptomatic CAVMs or risk factors, such as a family history of cerebral hemorrhage, treatment options are embolization, microsurgery, stereotactic radiation, or a combination of these modalities. Microsurgery for low-grade lesions (Spetzler-Martin grade I or II) can be effective. Spetzler-Martin grading scale estimates the risk of open surgery for cerebral AVMs. A grade 1 AVM describes a small, superficial lesion located in a non-critical area of the brain and is considered low risk for surgery. A grade 6 AVM is non-operable.[47] One series demonstrated a 100% obliteration rate with a 3.2% rate of neurologic deficits and 0% mortality with microsurgery.[48] 

Gamma knife surgery also has a similar risk profile with 100% obliteration rates for lesions < 1 mL in volume. For CAVMs that are poor surgical candidates, stereotactic radiosurgery can be considered but has a lower cure rate for larger lesions.[49] Embolization alone is ineffective in addressing CAVMs but could be a helpful adjunct with surgery or stereotactic radiation.

Differential Diagnosis

Bleeding from diseases like von Willebrand disease or hemophilia is more generalized and occurs in the setting of an injury. In contrast, bleeding from HHT is more localized to the malformed blood vessels. Several diseases share similar clinical manifestations to HHT and need to be ruled out during the workup. Referral to a hematologist can prove very helpful.

Limited Systemic Sclerosis

Patients with limited systemic sclerosis, called CREST syndrome, develop calcinosis, Raynaud disease, esophageal dysmotility, sclerodactyly, and telangiectasias. However, recurrent epistaxis is not a common feature of the syndrome. Specific autoantibodies may be positive in scleroderma, including anti-centromere antibody, anti-topoisomerase I (Scl-70), and anti-RNA polymerase III.[50]

Ataxia-Telangiectasia

Ataxia-telangiectasia is an autosomal recessive condition that presents with cerebellar atrophy with progressive ataxia, cutaneous telangiectasias, immune defects, and increased risk for malignancies. Symptoms typically occur in the first or second decade of life. Key features of this condition include elevated serum alpha-fetoprotein (AFP) and decreased total IgG and IgA.[51] 

Generalized Essential Telangiectasia

Generalized essential telangiectasia is a rare condition with both inherited and sporadic cases reported. The telangiectasias first appear on the lower extremities and slowly spread to involve the entire body.[52]

Hereditary Benign Telangiectasia

Hereditary benign telangiectasia is an autosomal dominant primary telangiectasia disorder with the development of telangiectasias on skin and lips during birth or childhood. Lesions are usually asymptomatic and do not have systemic involvement. Unlike in HHT, histology of hereditary benign telangiectasia demonstrates preserved skin and dilated vessels with thicker capillary walls, explaining the lack of hemorrhage.[53]

Rosacea

Rosacea is a common skin disorder with recurrent facial flushing, erythema, telangiectasias, and inflammatory pustules on the face. Etiological factors for the development of the condition include genetics, environmental factors, neurovascular deregulation, and microorganisms.[54]

Telangiectasia Macularis Eruptiva Perstans

Telangiectasia macularis eruptiva perstans is a rare form of mastocytosis. The condition is seen more frequently in adults. Telangiectatic macules manifest as flat, reddish-brown lesions on the skin due to infiltration of mast cells into the upper dermis. Systemic involvement may involve the bone marrow, GI tract, liver, and lymph.[55]

Dermatomyositis

Dermatomyositis is an idiopathic chronic inflammatory autoimmune disorder of the skin and muscles. Skin manifestations include heliotrope rash around the eyes, papules over digits, and periungual telangiectasias.[56]

Systemic Lupus Erythematosus (SLE)

Lupus erythematosus is a multi-organ autoimmune disease with varying clinical presentations. Cutaneous manifestations include a malar rash, oral and nasal ulcers, and periungual telangiectasias.[57]

Radiation Oncology

As discussed above, stereotactic radiation therapy has been used to manage cerebral AVMs as a single modality or in conjunction with microsurgery or embolization for larger lesions.[58] Gamma knife radiosurgery offers obliteration rates of 100% for AVMs smaller than 1 mL, 85% for 1 to 4 mL, and 58% for lesions > 4 mL. The risk of symptomatic radiation necrosis directly correlates with increasing AVM size.[59]

Medical Oncology

Dysfunctional angiogenesis is thought to play a role in the pathogenesis of HHT, and research has focused on whether anti-angiogenic substances and immunomodulatory agents can effectively treat HHT.

Bevacizumab is a humanized recombinant monoclonal antibody against vascular endothelial growth factor (VEGF), which is elevated in HHT. VEGF stimulates arterial, lymphatic, and venous development and suppresses endothelial cell apoptosis. Elevated VEGF levels can result in immature, abnormal vessel formation with constant remodeling.[60] Clinical trials and studies have explored the effectiveness of the VEGF inhibitor, administered systemically, topically, or submucosally, for control of HHT-related epistaxis.[61][62][63][64][65]

Double-blind, randomized control trials and other comparative studies evaluating both topical and intranasal submucosal bevacizumab demonstrate mixed conclusions when evaluating the severity of HHT-related epistaxis.[66] Two studies evaluating the submucosal application of bevacizumab demonstrated either a trend towards or significant improvement in epistaxis severity.[67] 

Primary risks associated with topical or submucosal injection of bevacizumab include septal perforation and osteonecrosis. In one clinical trial, systemic therapy with bevacizumab (5 mg/kg IV every two weeks for six treatments) demonstrated a reduction in epistaxis episodes and high cardiac output.[61] 

Side effects of systemic bevacizumab at oncologic doses (5 to 15 mg/kg) include GI perforation, hemorrhage, thromboembolism, poor wound healing, and reversible posterior leukoencephalopathy, which were not noted in the lower doses used to treat HHT. However, common adverse effects included hypertension, nausea, diarrhea, headache, and muscle or abdominal pain when used systemically.

Tacrolimus, a calcineurin inhibitor used for immunosuppression, has been shown to activate the ALK1-SMAD1/5/8 pathway and improve defects due to ALK1 loss.  

Thalidomide, an immunomodulatory imide drug, has been shown to downregulate VEGF levels in HHT, improve the integrity of vessel walls, and reduce epistaxis.[68][69][70] However, adverse effects, including neuropathy and fatigue, have limited its use as a therapeutic option.[32]  

Studies have evaluated the use of selective estrogen response modifiers (raloxifene, tamoxifen), progestins, and estrogens to reduce epistaxis and GI bleeding; however, findings are inconsistent.[32][71] Furthermore, potential side effects of hormone therapy, including gynecomastia, weight gain, and venous thromboembolism, have prevented its wide use as a treatment option. 

Prognosis

The literature evaluating the overall survival and prognosis of HHT is limited but may have a shorter expected lifespan. A retrospective study demonstrated lower median age of death in HHT versus non-HHT patients (63.2 vs. 70.0 years).[72] 

A more recent prospective study (n=675) found HHT patients to have poorer survival when compared to matched controls with a median age of death at 77 years versus 80 years.[17] Furthermore, the study found hazard ratios for death were highest within the first three years after HHT diagnosis and subsequently decreased. This decrease in HR could explain how HHT may be diagnosed after an acute complication such as a stroke. Early detection and screening of HHT and prevention of complications could help increase life expectancy.

Complications

HHT patients have a higher risk of bleeding and neurologic complications, including anemia, cerebral abscess, stroke, venous thrombosis, and heart failure.[17] [Table 1]

Table 1. Specific Complications Found in HHT and Recommended Prevention and Treatment

Postoperative and Rehabilitation Care

Scarring is a common complication after laser ablation or electrosurgical cauterization of intranasal telangiectasias due to loss of mucociliary clearance and subsequent crusting. Postoperative nasal hygiene with topical saline sprays and irrigations and deliberate postoperative debridement of crusts can prevent scarring and synechiae formation.

There are no definitive guidelines for optimal postoperative management after endovascular intervention or surgery for AVMs. Postoperative care, including activity restrictions, are based on the location of the AVM, size, the number of lesions, type of procedure (endovascular versus open), and extent of surgery.[73] Patients undergoing microsurgery for cerebral AVMs may require physical therapy after the procedure. Additional imaging may be necessary to assess embolization site and recurrence.[74]

Consultations

Since HHT affects multiple organ systems, adequate treatment of the condition requires multidisciplinary care. A referral to a hematologist is indicated to manage iron deficiency anemia and for anticoagulation if diagnosed with venous thromboembolism. For management of epistaxis, consider referral to an otolaryngologist. A gastroenterologist should be involved if there is a concern for GI bleeds.

HHT patients with pulmonary AVMs should be seen by a pulmonologist, interventional radiologist, or thoracic surgeon. Presence of a cerebral AVM warrants referral to a neurosurgeon. If embolization is not an option, an interventional radiologist or general surgeon should manage hepatic AVMs.

Deterrence and Patient Education

Affected individuals must receive education and counseling on the implication of a possible or definitive diagnosis of HHT. Given HHT is an autosomal dominant disease, it is essential to screen family members and provide genetic counseling prior to conception. Early diagnosis before patients are symptomatic can allow for screening tests and interventions to be done in a timely fashion and assist in diagnosing at-risk family members.[25]

Pearls and Other Issues

Early diagnosis of HHT is based on clinical findings. Genetic testing helps confirm the diagnosis but is not required for an index case unless 1) they are children who have not developed all the clinical features or 2) to test at-risk family members and identify a family-specific mutation. Screening and treatment of visceral AVMs depend on the potential for high-risk complications. For instance, proactive screening and treatment of asymptomatic pulmonary AVMs are encouraged compared to asymptomatic hepatic or cerebral AVMs.[25]

Enhancing Healthcare Team Outcomes

HHT can affect multiple organ systems, and early recognition and screening for clinical manifestations and prompt interventions can decrease morbidity and mortality.  Epistaxis is one of the most common presenting symptoms.  Patients with HHT benefit from a multidisciplinary approach and ideally should be referred to a center that specializes in HHT.