Hereditary Hemorrhagic Telangiectasia (Osler’s Disease)

Systemic, Interdisciplinary, Relatively Common—and Often Missed

Background: Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber disease, or Osler’s disease for short) is a systemic disease that can severely impair the quality of life and that requires interdisciplinary treatment. Among rare diseases, it is relatively common, with a prevalence of approximately 1/5000.

Methods: This review is based on publications retrieved by a selective literature search, including the two international guidelines on clinically relevant aspects of HHT.

Results: On average, about two decades elapse between the initial symptoms and the diagnosis of HHT. 95% of patients have nosebleeds; these usually begin before age 20 but can occur at any time, from infancy to old age. The diagnosis is usually made on clinical grounds on the basis of the characteristic telangiectases, a positive family history, and possible involvement of the gastrointestinal tract, lungs, liver, and brain. Nosebleeds can sometimes be reduced by outpatient measures including counseling on keeping the nose moist (expert consensus), self-application of a nasal packing (which improves the quality of life, according to an online survey), and the prescription of tranexamic acid (reduction of nosebleeds from 17.3% [5.5; 27.6] to 54%). In particular, screening (expert consensus) for pulmonary vascular malformations (frequency 10–50%) can prevent many adverse outcomes. If pulmonary vascular malformations cannot be ruled out, antibiotic prophylaxis is recommended before medical procedures that can cause bacteremia (expert consensus).

Conclusion: Broad awareness of the condition, early diagnosis, and interdisciplinary treatment improve the quality of life and ultimate outcome of persons with HHT. Nevertheless, there are few options supported by good evidence for the appropriate treatment of this rare, often serious disease..

Hereditary hemorrhagic telangiectasia (HHT) is characterized by pathological widening of vessels between arteries and veins. Cutaneous and mucosal telangiectases or large vascular malformations of internal organs arise. Dilatation of the vessels disrupts the capillary filter. Bleedings can result, especially from the nose and the gastrointestinal tract. Problems can also develop due the shunting itself. Although HHT, with an estimated prevalence of approximately 1/5000, is relatively common in comparison with many other rare diseases, it is often not detected until it reaches an advanced stage: in Germany 18 years elapse, on average, between the first signs of disease and the diagnosis of HHT (1). However, early detection is important for those affected, because only an efficient combination of screening and treatment normalizes the otherwise reduced life expectancy (73.3 years versus 76.7 years) (2, 3). The aim of this review is to present the essential aspects of the clinical presentation, diagnosis, and treatment of HHT.

Method

The first step was a selective survey of the literature in PubMed (www.pubmed.gov) including the international guidelines (4, 5). We adopted the classification of evidence used in the guidelines: level of evidence (LoE) from low = III to high = I (5, 6), GRADE quality of evidence (QoE) from very low to high (4, 7). Two meta-analyses of drug treatment (8, 9) found partly contradictory results, so the individual studies are reported. The findings of randomized controlled trials are presented in tabular form in the body of the article (Table), and online (eTable 1), a selection of further studies online (eTable 2).

Table

A selection of randomized controlled trials on the medical treatment of epistaxis and the need for transfusion in hereditary hemorrhagic telangiectasia

eTable 1

Continuation of Table: A selection of randomized controlled trials on the treatment of hereditary hemorrhagic telangiectasia

eTable 2

A selection of non-randomized studies and case reports on drug treatment of hereditary hemorrhagic telangiectasia*

Diagnosis

Traditionally terms such as Osler’s disease, Rendu–Osler–Weber syndrome, and variants thereof were used, but recently these have been replaced by hereditary hemorrhagic telangiectasia (HHT). This term brings together three important aspects of the illness which, together with visceral involvement, form the four current clinical Curaçao criteria for diagnosis of the disease (Box, Figure 1) (10). The four sides of the rectangle in Figure 1 provide a useful aide memoire to these four diagnostic criteria, which at the same time are the most important facets of the clinical presentation: three sides represent H + H + T, while the fourth side shows the visceral component.

Box

The clinical criteria (so-called Curaçao criteria)

Figure 1

Overview of the principle manifestations

International guidelines often recommend molecular genetic diagnostic techniques (5), but country-specific features have to be noted. For instance, some German health insurance providers will not cover the costs of molecular genetic diagnostic techniques in clinically confirmed cases of HHT. Currently, probably for reasons related to technical issues, in up to 15% of cases no relevant familial mutations are found despite a typical presentation. Furthermore, due to the terms of the German Genetic Diagnosis Act, detection of mutations, especially in asymptomatic or only slightly symptomatic persons, can lead to difficulties with insurance policies. The nationwide German Osler’s Disease Self-Help Association offers independent information and advice in German (www.morbus-osler.de).

Pathophysiology and genetics

The current thinking on the development of HHT is that vascular widening occurs in a normal capillary bed together with postcapillary dilatation of venules and a reduction in the number of adjacent capillaries. Increasing widening leads to direct shunts between arteries and veins, manifesting as telangiectases or—on a larger scale—vascular malformations.

Mutations in different genes relating to the transforming growth factor β signaling pathway give rise to different phenotypes. Endoglin (ENG; HHT1) and activin receptor-like kinase 1 (ALK1, ACVRL1; HHT2) are most often involved (11). HHT1 is frequently associated with pulmonary and cerebral vascular malformations, while HHT2 principally evokes hepatic vascular malformations. Particularly in HHT2, occasional cases of pulmonary arterial hypertension (PAH) may occur. One important special case is a syndrome combining juvenile polyposis and HHT (JPHT, mutation of the SMAD4 gene). Juvenile polyposis is the leading component of the syndrome owing to the danger of malignant transformation, and therefore takes first place in the name. For both PAH and JPHT, referral to a center of expertise in these diseases is advisable. The peculiar characteristics of manifestations of HHT at various sites are described in the following sections.

Lungs

Pulmonary arteriovenous malformations (PAVM, Figure 1.4 b) occur in 10–50% of persons with HHT (5, 11). PAVM often remain clinically silent for a long time, or merely cause headaches, but can then suddenly have catastrophic consequences such as paradoxical embolisms and resulting infarcts (especially of the brain) and abscesses (brain, liver, spleen) (eCase report). They are thought to be responsible for the reduced life expectancy in unscreened populations (2). This is the reason why international guidelines recommend screening for PAVM in all patients with confirmed or suspected HHT (LoE: III) (4, 5).

Until the presence of PAVM is excluded in a person in this category, prophylactic antibiotics should be given in every case of an intervention with the potential for bacteremia, analogous to the current recommendations for prevention of infectious endocarditis (LoE: III) (4, 5). One example of such a procedure is professional tooth cleaning.

The method of choice for screening is bubble contrast echocardiography (see the Figure in the eCase report; sensitivity 97%, specificity 77% compared with computed tomography) (12) (LoE: II). This modality assesses how much of the contrast medium—which does not pass through the capillary filter—reaches the left heart cavities (13). An alternative screening technique is thoracic computed tomography. Owing to the associated radiation exposure and the inability to detect so-called microscopic shunts, however, this method is often employed only to clarify if embolization is possible. Simple chest radiography does not suffice for screening purposes. Currently repetition after around 5 years is recommended. The treatment of choice is percutaneous catheter embolization (LoE: II) of all technically attainable PAVM (14). Only in extremely rare cases does surgical resection make sense. PAVM may seldom—in pregnant women, somewhat more often—lead to potentially fatal bleeding and thus to hemoptysis or hemothorax. Women who intend to become pregnant should therefore be screened and given information about warning signs (QoE: moderate) (4).

Another lung manifestation is pulmonary hypertension, which may occur “secondarily” as a consequence of hepatic involvement or, occasionally, “primarily” as PAH (see above).

Central nervous system

The majority of neurological symptoms in patients with HHT result from paradoxical embolization by PAVM. Cerebral vascular malformations (CVM), found in around 10–23% of patients (5, 11), comprise arteriovenous malformations, fistulas, and telangiectases. The risk of symptomatic hemorrhage is thought to be lower than with sporadic CVM.

The therapeutic management is often conservative and each individual case should be explored by an interdisciplinary team at a center with the appropriate expertise (5). Whether and when screening for CVM by means of magnetic resonance imaging should be carried out is controversial (LoE: III, QoE: low) (4, 5, 15). The HHT working group of the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) recommends discussion of the various options with the patient (16).

Spinal vascular malformations are much rarer, and screening is not recommended. Given the anatomical circumstances, the risk of complications from epidural or peridural anesthesia is negligible, so the latter (e.g., during parturition) can be given without prior examination of the spinal canal (QoE: low) (4).

Liver

Hepatic vascular malformations (HVM) can be detected by imaging in 32–78% of patients with HHT, but become symptomatic in only 8% of cases (5, 11). Symptomatic HVM usually develop slowly, so it is controversial whether screening should be recommended (QoE: low) (4, 5, 15). The three classic clinical forms—hyperdynamic heart failure (due to the scale of the shunt volume: clinically impaired performance, dyspnea), portal hypertension (often with increased gastrointestinal hemorrhage, ascites), and biliary (jaundice, abdominal pain)—may overlap. Secondary pulmonary hypertension may occur, as may lesions suggestive of focal nodular hyperplasia. The diagnosis is usually established by means of Doppler sonography, otherwise by contrast-enhanced computed tomography or magnetic resonance imaging (LoE: III, QoE: high). Biopsies should be avoided (LoE: III).

The treatment of symptomatic liver involvement is frequently complex (4, 5). Especially in hyperdynamic heart failure one can consider starting with β-blockers and diuretics, moving on to bevacizumab (off label) if the initial treatment is unsuccessful (QoE: moderate, response rates approximately 60–75%) (4, 17, 18). In the case of rapid deterioration, prompt liver transplantation may be necessary (QoE: moderate) so as not to miss the therapeutic window for this intervention. Hepatic embolization can be successful in experienced hands, but is controversial due to the relatively frequent and potentially fatal complications (LoE: III) (4, 5, 19).

Gastrointestinal tract

Mucosal telangiectases of the stomach and bowel occur in up to 91% of patients with HHT, but bleed in only 30%, rarely before the age of 40 years (4). The patients are often accustomed to melena and anemia due to swallowing blood from the nose, so even massive intestinal bleeding may go unnoticed. For this reason, those affected are recommended to undergo determination of their hemoglobin concentration at least once each year (LoE: III) (5). In the event of discrepancy with episodes of epistaxis, gastrointestinal endoscopy is advisable. Argon plasma coagulation can be tried initially (LoE: III, QoE: low). If success is not achieved, antifibrinolytics such as tranexamic acid (off label; QoE: low) and hormones, e.g., estrogen/gestagen therapy, come into question (LoE: III) (20). If these approaches fail, one can switch to antiangiogenetic treatment with bevacizumab (off label) (QoE: moderate) (Table) (4, 21).

Nosebleeds

Epistaxis is the most commonly occurring symptom, affecting approximately 95% of patients with HHT. Nosebleeds generally occur around the age of puberty, but vary with regard to the time of onset and the course they take. From the pathophysiological viewpoint, there is an underlying triad of poor protection (thin respiratory epithelium, sometimes in direct contact with cartilage or bone without an intermediate layer of soft tissue), recurring trauma (airflow, dryness, dust particles, mobile crusts), and vulnerable telangiectases (whose development is thought to be triggered by the episodes of trauma) (22, 23). Many approaches to prevention and treatment address these three factors. The currently prevailing guidelines recommend a three-step procedure, which we have updated and modified (Figure 2). The multiplicity of measures adopted (eTables 1 and 2) shows that no optimal treatment exists. The best approach is often determined by a process of testing, adjusting, and tweaking in cooperation with the patient. The primary goal is to minimize the trauma by moistening the nasal mucosa (LoE: III; QoE: moderate). The possible approaches include, among others, inhalation, application of an oil, ointment, or gel, irrigation, and use of a humidifier. Admixed propranolol (24) or tacrolimus (25) (off label in each case) can enhance the efficacy of ointments and gels; whether other medications can be beneficial in this way is controversial (26, 27, 28) (eTables 1 and 2). Temporary occlusion with plaster strips, nasal olives, or moistened cotton batting can also increase the humidity and simultaneously stop the flow of air (29). The duration of the nosebleeds has a detrimental effect on the quality of life of those affected, as patients might experience loss of control and worry about bleeding to death (30). It has proved helpful to show patients how they can stop anterior nose bleeds by external compression. A nose clip can be used (our recommendation, in analogy to the clinical practice in general nosebleeds [31]), or they can learn to apply a nasal packing themselves. This latter method has been shown to lead to enhancement of quality of life (mean improvement between 0.7 and 10.8, as measured online using the Glasgow Benefit Inventory for self-packing) (32). The next-level treatment recommended in the guidelines is oral administration of tranexamic acid (up to three 1-g doses (QoE: high), which is approved for this indication in Germany (33, 34) (Table). Another interesting option is off-label use of N-acetylcysteine 600 g 3× daily, as this substance has minimal side effects and can be bought over the counter. This treatment has been shown to bring about a significant reduction in the frequency of epistaxis: 1.11 versus 1.35 episodes per day (35). N-Acetylcysteine is thought to exert its effect by virtue of being an antioxidant.

Figure 2

Sequential approach for the treatment of epistaxis in hereditary hemorrhagic telangiectasia

On the same level are the options for endonasal coagulation (QoE: moderate) (4). To date the Nd:YAG laser has often been used, but there has been no conclusive comparison of the efficacy of the various methods. One study of laser coagulation described a significant decrease in the mean daily bleeding time over a 2-week period from 135 minutes before treatment to 46 minutes after 6.5 months (36). The authors of review articles view the simultaneous endonasal injection of bevacizumab (off label, eTable 1) as obsolete (37, 38). The guidelines also mention endonasal sclerotherapy by means of local injection. This treatment option has been in use for a long time and is efficacious, but is controversial due to the danger of blindness (39). The risk is low, and to the best of our knowledge has never been quantified, but the first author knows of two cases. The frequency of transient visual loss after intranasal steroid injections has been estimated at 6/99 500 (0.006%) (40). The rate is likely to be higher with sclerosing agents owing to their mechanism of action.

The next level of medication is antiangiogenetic treatment, e.g., with intravenous bevacizumab (off label) (QoE: moderate). In a retrospective study of 238 persons, the Epistaxis Severity Score (ESS) (e1) went down from 6.8 to only half as much (e2). A double-blind randomized controlled trial did not confirm this finding, but that may be due to the low number of patients included (21) (Table). Bevacizumab cannot be given by mouth, and in the outpatient setting in Germany the patient’s health insurance fund has to agree in advance to cover the costs. Bevacizumab is associated with adverse effects such as thrombosis (2%; e2) and possibly a fatality (e3). Nothing is yet known about the long-term effects in this population (e4). The guidelines include thalidomide, which is also effective, on the same level, but we are cautious in this regard due to the very pronounced adverse effects (particularly neuropathy) in around 50% of cases (e5). A recently published abstract of a double-blind randomized placebo-controlled trial describes ESS reductions of 1.84 for pomalidomide and 0.89 for placebo after 24 weeks (e6). However, long-term observation has yet to be completed. We prefer tamoxifen (off label) (e7) (Table).

Also on this level are two surgical procedures: septodermoplasty according to Saunders (QoE: low; mean number of blood transfusions 1 year before operation and thereafter: 21 versus 1) (e8) and nasal closure according to Young (QoE: moderate; complete cessation of epistaxis in 30 of 36 cases) (e9) (4). In septodermoplasty the affected area of nasal mucosa is removed nearly in toto and replaced with transplanted skin or mucosa. The adverse effects include marked nasal incrustation, sometimes ozena, difficulty in breathing through the nose, loss of the sense of smell, and recurrence of bleeding at sites that are difficult to treat. Septodermoplasty is therefore used only rarely or in modified form. Unlike septodermoplasty, complete nasal closure is usually reversible. Its disadvantages are loss of both the sense of smell and the ability to breathe through the nose. To date, however, total nasal closure is the only method that yields lasting complete abolition of epistaxis. It is also effective if anticoagulation or inhibition of platelet aggregation is necessary. One study found that the reduction of blood loss resulted in an increase of more than 4.5 g/dL in hemoglobin concentration and distinct enhancement of quality of life (e9).

Further aspects

Adult patients and also children with hemorrhage or signs of anemia should be tested for anemia and iron deficiency (QoE: high) and, if necessary, treated accordingly (QoE: low to moderate) (4). It is very important to be aware that bleeding in HHT is not an absolute contraindication to anticoagulation or inhibition of platelet aggregation (QoE: low). Dual platelet aggregation inhibition or combination with anticoagulation should, however—if possible—be avoided (QoE: low) (4).

The management of pregnant women with HHT has already been addressed above. If untreated CVM or PAVM are present, or if the latter have not recently been excluded by screening, the recommended procedure is to categorize the pregnancy as high-risk and refer the patient for management by a multidisciplinary team experienced in HHT at a tertiary care center (QoE: very low) (4).

Cutaneous and mucosal telangiectases can bleed and stigmatize. Treatment with Nd:YAG laser or any other coagulation technique is usually successful (e10) (eTable 1). Those affected and caretakers can find further information at the following websites: www.morbus-osler.de (in German), www.curehht.org, www.vascern.eu.

Dedication

In memoriam Klaus Hanselmann (24.08.1942–04.01.2024), the founder of the German Osler’s Disease Self-Help Association (Morbus Osler-Selbsthilfe e.V.).

Conflict of interest statement
UG has received reimbursement of travel costs from the German Osler’s Disease Self-Help Association. He is chair of the board of trustees of the Osler Foundation and member of the Global Research and Medical Advisory Board of Cure HHT.

The remaining authors declare that no conflict of interest exists.

Received on 1 December 2023, revised version accepted on 16 May 2024

Translated from the original German by David Roseveare

Corresponding author
Prof. Dr. med. Urban Geisthoff

Klinik für Hals-, Nasen- und Ohrenheilkunde, Kopf- und Hals-Chirurgie

Universitätsklinikum Marburg

Baldingerstr.

35043 Marburg, Germany

Cite this as:
Geisthoff UW, Mahnken AH, Denzer UW, Kemmling A, Nimsky C, Stuck BA: Hereditary hemorrhagic telangiectasia (Osler’s disease): systemic, interdisciplinary, relatively common—and often missed. Dtsch Arztebl Int 2024; 121: 601–7. DOI: 10.3238/arztebl.m2024.0111

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