Katharine J. Henderson

Liver Disease in Patients with Hereditary Hemorrhagic Telangiectasia

BACKGROUND Hereditary hemorrhagic telangiectasia, or Rendu-Osler-Weber disease, is an autosomal dominant disorder characterized by angiodysplastic lesions (telangiectases and arteriovenous malformations) that affect many organs. Liver involvement in patients with this disease has not been fully characterized. METHODS We studied the clinical findings and results of hemodynamic, angiographic, and imaging studies in 19 patients with hereditary hemorrhagic telangiectasia and symptomatic liver involvement. RESULTS We evaluated 14 women and 5 men who ranged in age from 34 to 74 years. All but one of the patients had a hyperdynamic circulation (cardiac index, 4.2 to 7.3 liters per minute per square meter of body-surface area). In eight patients, the clinical findings were consistent with the presence of high-output heart failure. The cardiac index and pulmonary-capillary wedge pressure were elevated in the six patients in whom these measurements were performed. After a median period of 24 months, the condition of three of the eight patients had improved, four were in stable condition with medical therapy, and one had died. Six patients had manifestations of portal hypertension such as ascites or variceal bleeding. The hepatic sinusoidal pressure was elevated in the four patients in whom it was measured. After a median period of 19 months, the condition of two of the six patients had improved, and the other four had died. Five patients had manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging. After a median period of 30 months, the condition of two of the five had improved, the condition of one was unchanged, heart failure had developed in one, and one had died after an unsuccessful attempt at liver transplantation. CONCLUSIONS In patients with hereditary hemorrhagic telangiectasia and symptomatic liver-involvement, the typical clinical presentations include high-output heart failure, portal hypertension, and biliary disease.

Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations

PURPOSE To assess long-term clinical and imaging results of technically successful pulmonary arteriovenous malformation (AVM) embolization. MATERIALS AND METHODS One hundred fifty-five patients with pulmonary AVMs underwent embolization during a period of 3 years. Recommended follow-up included clinical assessment, helical computed tomography, and physiologic evaluation within 1 year and then every 5 years. RESULTS Hereditary hemorrhagic telangiectasia was present in 148 patients (95%). Four hundred fifteen pulmonary AVMs were occluded during 205 procedures. Clinical follow-up was available in all patients over 3-7 years and imaging follow-up was available in 144 patients (393 lesions) over 1-7 years (mean, 2.9 y). Problems related to pulmonary AVMs occurred in 35 patients (23%) at 42 time points: 22 patients with 23 symptomatic events and 17 patients with 19 asymptomatic events. Symptoms resulted from growth of nonembolized pulmonary AVMs (n = 19), residual embolized pulmonary AVMs (n = 5), or both (n = 2). Symptoms consisted of respiratory manifestations (n = 13), cerebral ischemia (n = 4), brain abscess (n = 5), hemoptysis (n = 3), and seizure (n = 1). Imaging showed pulmonary AVM involution in 97% of embolized lesions and 11 residual lesions (2.8%) in 10 patients (6.9%). These were caused by recanalization (n = 7), presence of an accessory feeding artery (n = 1), pulmonary collateral vessels (n = 1), and bronchial collateral vessels (n = 2). CT detected 10 of the 11 residual lesions. Imaging detected 97 previously small pulmonary AVMs that had enlarged to a significant size in 28 patients (18%), 15 of whom were symptomatic and 13 of whom were asymptomatic. CONCLUSIONS Clinical and anatomic evaluation after pulmonary AVM embolization is important to detect persistent or reperfused lesions and enlarging lesions, with the latter more common. Patients with persistent, reperfused, or enlarging lesions often have symptoms, but a significant minority of patients are asymptomatic. More frequent assessment may improve detection before the onset of symptoms.

Long-Term Outcome of Embolotherapy and Surgery for High-Flow Extremity Arteriovenous Malformations

PURPOSE To assess the long-term efficacy of embolotherapy in combination with surgery for management of symptomatic high-flow arteriovenous malformations (HFAVMs) of the lower and upper extremities. MATERIALS AND METHODS Twenty consecutive patients with symptomatic high-flow lower extremity AVMs (LE-AVMs; n = 9) and upper extremity AVMs (UE-AVMs; n = 11) were treated from 1982 to 1999. All nine patients with LE-AVM had pain and seven had ulceration of the skin. All 11 patients with UE-AVM had debilitating pain, seven had weakness of the affected hand, and two had bony erosion. Embolization of the nidus beneath the site of maximum pain or ulceration was performed percutaneously from the femoral artery through coaxially placed microcatheters (n = 18) or surgical cutdown (n = 2). Cyanoacrylate (isobutyl or n-butyl) diluted with iophendylate or ethiodized oil was used in 19 of 20 patients. RESULTS Follow-up was completed in eight of nine patients with LE-AVM (mean, 8.6 y) and nine of 11 patients with UE-AVM (mean, 7.4 y) after treatment. One patient with localized LE-AVM was functioning well 13 years after embolotherapy and another was functioning well 16 years after undergoing three embolotherapy procedures and two skin grafts. Five of nine patients with LE-AVM required below-the-knee (n = 4) or above-the-knee (n = 1) amputation 1-6 years after technically and clinically successful embolotherapy. All three trifurcation arteries were diffusely involved in HFAVM in patients requiring amputation. Healing of the two amputation sites, involved by AVM at the knee, was excellent after preoperative geniculate artery embolotherapy. All 11 patients with UE-AVM experienced marked symptomatic improvement; seven after embolotherapy alone and the other four after resection of AVM. One complication of digital spasm was reversed by administration of nerve blocks. CONCLUSIONS LE-AVM with diffuse involvement of all three trifurcation arteries ultimately required amputation because of recurrence of symptoms after technically and clinically successful embolotherapy. Cyanoacrylate embolotherapy alone or in combination with surgical resection of the AVM provided excellent long-term palliation in patients with UE-AVM.

Diagnosis and Management of Gastrointestinal Bleeding in Patients With Hereditary Hemorrhagic Telangiectasia

OBJECTIVE:Our aim was to report our experience with treating GI bleeding in patients with hereditary hemorrhagic telangiectasia (HHT).METHODS:Consecutive patients with GI bleeding referred to the Yale University Vascular Malformation Center underwent clinical evaluation and endoscopy. Hb and blood transfusion requirements for 1 yr before and after evaluation were documented. Patients with a mean Hb ≤ 8 mg/dl or blood transfusion requirements ≥ 12 units packed red blood cells (PRBC)/yr were defined as patients with significant bleeding. Drug therapies, including ethinyl estradiol/norethindrone, danazol, and aminocaproic acid, were prescribed on an individual patient basis.RESULTS:The study included 43 HHT patients with a mean age of 57 yr. Endoscopy revealed telangiectases in the esophagus (1/41), stomach (33/41), duodenum (33/41), jejunum (5/9), and colon (10/32). Patients with > 20 telangiectases visualized on esophagogastroduodenoscopy had a significantly lower mean Hb of 7.9, compared with 9.4 (P = 0.007), and a trend toward higher blood transfusion requirements. Non–HHT-related causes of GI bleeding were diagnosed in four patients. During a mean follow up of 18.9 months, the group of 40 patients with HHT-related bleeding had improvements in their mean Hb and blood transfusion requirements.CONCLUSIONS:Some HHT patients with GI bleeding improve on drug therapies, but others fail. Transfusion-dependent GI bleeding is difficult to manage, and optimal management may include both medical and endoscopic treatments.

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP–HHT syndrome†

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP–HHT was described that is also caused by mutations in SMAD4. Although both JP and JP–HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP–HHT patients were clustered in the COOH‐terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre‐symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP–HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP–HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP–HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP–HHT and monitored accordingly.

New Definition and Natural History of Patients With Diffuse Pulmonary Arteriovenous Malformations: Twenty-Seven–Year Experience

BACKGROUND Patients with diffuse pulmonary arteriovenous malformations (PAVM), a small but important subset of the PAVM population, have significant morbidity and mortality rates. METHODS Thirty-six patients (21 female and 15 male) with diffuse PAVM from a cohort of 821 consecutive patients with PAVM were evaluated. Diffuse PAVM were categorized angiographically: involvement of one or more segmental pulmonary arteries in one or both lungs. Hereditary hemorrhagic telangiectasia (HHT) status, gender, presence or absence of large (> or = 3-mm diameter artery) focal PAVM, oxygen saturations, complications including hemoptysis, years of follow-up, and survival were tabulated. RESULTS HHT was present in 29 of 36 patients (81%), and diffuse PAVM were more commonly bilateral (26 of 36 patients, 72%) than unilateral (10 of 36 patients, 28%) [p = 0.02]. Female gender was associated with bilateral diffuse PAVM (19 of 26 patients, 73%) [p = 0.01]. Focal PAVM were present in both groups but more commonly in patients with bilateral involvement (16 of 26 patients, 62%) [p = 0.02]. Initial oxygen saturations (pulse oximetry, standing) of patients with unilateral and bilateral diffuse PAVM were 87 +/- 7% and 79 +/- 8% (mean +/- SD), respectively (p = 0.02). The last or current values for patients with unilateral and bilateral involvement are 95 +/- 3% and 85 +/- 7%, respectively (p < 0.0001). Nine deaths occurred, and all were in patients with bilateral involvement. Deaths were due to hemoptysis of bronchial artery origin (n = 2), hemorrhage from duodenal ulcer (n = 1), spontaneous liver necrosis (n = 3), brain hemorrhage (n = 1), brain abscess (n = 1), and operative death during attempted lung transplant (n = 1). CONCLUSIONS Patients with diffuse PAVM are a high-risk group, and yearly follow-up is recommended.

ORIGINAL RESEARCHPULMONARY VASCULAR DISEASENew Definition and Natural History of Patients With Diffuse Pulmonary Arteriovenous Malformations: Twenty-Seven–Year Experience

BACKGROUND Patients with diffuse pulmonary arteriovenous malformations (PAVM), a small but important subset of the PAVM population, have significant morbidity and mortality rates. METHODS Thirty-six patients (21 female and 15 male) with diffuse PAVM from a cohort of 821 consecutive patients with PAVM were evaluated. Diffuse PAVM were categorized angiographically: involvement of one or more segmental pulmonary arteries in one or both lungs. Hereditary hemorrhagic telangiectasia (HHT) status, gender, presence or absence of large (> or = 3-mm diameter artery) focal PAVM, oxygen saturations, complications including hemoptysis, years of follow-up, and survival were tabulated. RESULTS HHT was present in 29 of 36 patients (81%), and diffuse PAVM were more commonly bilateral (26 of 36 patients, 72%) than unilateral (10 of 36 patients, 28%) [p = 0.02]. Female gender was associated with bilateral diffuse PAVM (19 of 26 patients, 73%) [p = 0.01]. Focal PAVM were present in both groups but more commonly in patients with bilateral involvement (16 of 26 patients, 62%) [p = 0.02]. Initial oxygen saturations (pulse oximetry, standing) of patients with unilateral and bilateral diffuse PAVM were 87 +/- 7% and 79 +/- 8% (mean +/- SD), respectively (p = 0.02). The last or current values for patients with unilateral and bilateral involvement are 95 +/- 3% and 85 +/- 7%, respectively (p < 0.0001). Nine deaths occurred, and all were in patients with bilateral involvement. Deaths were due to hemoptysis of bronchial artery origin (n = 2), hemorrhage from duodenal ulcer (n = 1), spontaneous liver necrosis (n = 3), brain hemorrhage (n = 1), brain abscess (n = 1), and operative death during attempted lung transplant (n = 1). CONCLUSIONS Patients with diffuse PAVM are a high-risk group, and yearly follow-up is recommended.

Outcome of Septal Dermoplasty in Patients With Hereditary Hemorrhagic Telangiectasia

Objectives/Hypothesis: Septal dermoplasty has been recommended as the treatment of choice for life‐threatening epistaxis in patients with hereditary hemorrhagic telangiectasia. The purpose of the study was to evaluate the effectiveness and outcomes of septal dermoplasty for management of transfusion‐dependent epistaxis.

Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene–phenotype correlations†‡

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disease with a wide spectrum of vascular malformations (VMs) involving multiple organs. Nine to 16% of patients with HHT harbor brain arteriovenous malformations (AVMs), which can cause intracranial hemorrhage (ICH). Our objective was to study clinical manifestations of brain AVMs in patients with HHT and correlate these with the specific gene mutated. We reviewed records of 171 patients with HHT and brain AVMs. A history of ICH was found in 27% (41/152) patients, with a mean age of 26 ± 18 range, (0–68) years. All of patients with ICH were neurologically asymptomatic prior to ICH. Multiple brain AVMs were found in 23% (170/39) of patients on initial examination. Genetic test results were available in 109 (64%) patients. Mutations in ENG, ACVRL1, and SMAD4 were present in 75 (69%), 18 (17%), and 2 (2%), respectively. A history of ICH was reported in 24% of patients with an ENG mutation and 27% of patients with an ACVRL1 mutation, with a mean age of 26 ± 16 (range, 2–50) and 18 ± 21 (0–48) years, respectively. No statistically significant differences in age at first brain AVM diagnosis, prevalence of ICH history, age at ICH, or other manifestations of brain AVMs were observed among gene groups. In conclusion, no evidence for differences in brain AVM characteristics was observed among HHT gene groups, although we cannot exclude clinically important differences. Larger studies are needed to further guide brain AVM screening decisions in patients with HHT.

Septectomy and septal dermoplasty for the treatment of severe transfusion-dependent epistaxis in patients with hereditary hemorrhagic telangiectasia and septal perforation.

Background Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal angiogenesis with resultant telangiectasia formation in mucocutaneous tissues, visceral organs, and the central nervous system. The most common manifestation of HHT is epistaxis resulting from trauma to thin-walled telangiectasias. Many patients with HHT experience worsened epistaxis due to the presence of a septal perforation. Septal perforation in HHT patients results from aggressive noncartilage sparing treatments such as monopolar cauterization. Although the mainstay of treatment for patients with severe transfusion-dependent HHT remains to be septal dermoplasty (SD), patients with a septal perforation are less likely to have a successful outcome. In this small subset of patients, septectomy (ST) combined with SD is proposed to eliminate this variable to improve skin graft uptake and therefore outcome. This study reviews the indications, procedure, and outcome of nine patients with severe transfusion-dependent HHT and septal perforation who underwent the combined procedure of SD/ST. Methods Nine HHT patients with severe transfusion-dependent epistaxis and septal perforation underwent SD/ST at our institution over a 5-year period. Quality of life, including number of daily events of epistaxis, and transfusion requirements were determined before and after surgery. Technical aspects of the procedure as well as complications were reviewed. Results The combined procedure of SD/ST resulted in a long-lasting subjective improvement in quality of life for all patients. Similarly, transfusion requirements were reduced from 22.61 to 9.57 (p < 0.05). There were no complications or increased morbidity from the procedure. Conclusion Combined SD/ST is a safe and effective treatment for HHT patients with transfusion-dependent epistaxis and septal perforation.