Hepatic Arteriovenous Malformations Research Articles

Phenotypic characterisation of SMAD4 variant carriers

BackgroundBoth hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective...

Thick tiny hearts and tangled vessels: Navigating the complexity of a neonate with hepatic arteriovenous malformation, hypertrophic cardiomyopathy, and persistent pulmonary hypertension

ABSTRACT Congenital hepatic arteriovenous malformation (HAVM) is an uncommonly encountered condition in clinical practice. This condition often presents as isolated hepatomegaly, congestive cardiac failure or anemia. Here, we discuss a case of a full-term neonate who was admitted to the neonatal care unit for birth asphyxia and neonatal sepsis and was consecutively diagnosed with HAVM and hypertrophic cardiomyopathy, along with persistent pulmonary hypertension.

Long Term Survival of Heritable Pulmonary Arterial Hypertension Associated with Hereditary Hemorrhagic Telangiectasia: A Case Series.

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary disease characterized by recurrent epistaxis, mucocutaneous telangiectasias, and visceral arteriovenous malformations. Multiple genetic mutations have been linked to this rare disease, including ENG, ALK1 (ACVRL1), and MADH4. Pulmonary hypertension is a potential complication of HHT, with the most common phenotypes being World Health Organization (WHO) group 1 heritable pulmonary arterial hypertension (PAH), which is typically associated with ALK1 mutation; WHO group 2 pulmonary hypertension due to high output heart failure from hepatic arteriovenous malformations and/or anemia; and WHO group 2 due to high pulmonary artery wedge pressure. There is scarce evidence to help guide treatment of heritable PAH in HHT, and observational literature suggests that patients with HHT and heritable PAH have a worse prognosis compared to patients with idiopathic PAH. We describe the diagnosis, pulmonary hemodynamics, and detailed treatment courses of three patients with ALK1-associated HHT and PAH, who all exhibited objective clinical improvement with parenteral prostacyclins and oral agents.

Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia: Long-term results of endoscopic treatment.

Background and study aims This longitudinal prospective study evaluated the long-term outcome of endoscopic treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectases (HHT), its safety and outcome predictors. Patients and methods Consecutive patients with HHT and either anemia disproportionate to epistaxis or overt gastrointestinal bleeding received endoscopic treatment of gastrointestinal telangiectases with argon plasma coagulation (APC). Hemoglobin levels and transfusion requirements were evaluated before and after treatment. Treatment effectiveness was classified as: 1) complete: hemoglobin level during the follow-up ≥9 g/dL; 2) complete with recurrence: hemoglobin ≥9 g/dL for at least 12 months with subsequent drop to <9 g/dL; or 3) absent: no improvement of hemoglobin level. Adverse events (AEs) were classified as mild, moderate, severe or fatal. Correlations were searched between treatment outcome and demographic/genetic characteristics, number, size and site of telangiectases, and hepatic arterio-venous malformations grade. Results Forty-seven patients with HHT were enrolled. At median follow-up of 134 months (range 20-243 months), 41 of 47 patients showed treatment response (complete or with recurrence) after one (14/47) or more (27/47) endoscopic treatments. Median hemoglobin levels were 7.0 g/dL and 11.9 g/dL at baseline and at the end of follow-up, respectively. Transfusion requirement decreased from 22.8 to 7.3 red cell unit/year. A higher baseline number of telangiectases was associated with a lower chance of response ( P =0.008). Only one severe AE (0.4%, jejunal perforation) was recorded. Conclusions Endoscopic treatment of gastrointestinal teleangiectases for gastrointestinal bleeding in patients with HHT is effective in the long term and safe.

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high-output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left-sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

Congenital Hepatic Arteriovenous Malformation: Often Missed Cause for Neonatal Pulmonary Arterial Hypertension

Congenital hepatic arteriovenous malformations (AVM) are extremely rare, with an incidence of less than 1 in 1 hundred thousand, and the literature is limited to only a few case reports. They are characterised by an abnormal arterial connection to a fistulous venous connection within the liver. This results in high flow, low resistance circulation that causes high output cardiac failure. We report a late-preterm male newborn who presented with respiratory distress and signs of cardiac failure on day 1 of life. The newborn is diagnosed with hepatic AVM as the cause of severe pulmonary arterial hypertension (PAH) and cardiac failure. This case report, along with the literature review, emphasises the need for a high index of suspicion to look for hepatic AVM in a newborn presenting with unexplained PAH and cardiac failure and also discusses different management strategies for hepatic AVM.

Hepatic arteriovenous malformation in a calf

A case of hepatic arteriovenous malformation is described in a calf that presented with a marked increase in abdominal volume and died 12 h after birth. At necropsy, the calf had marked abdominal distension and haemoperitoneum. The left hepatic lobe was reduced in size and covered by slightly whitish and intensely vascularized membranous tissue. At the edge of the left lobe there were cystic structures filled with translucent fluid. On cut surface, there were multiple cavitations well delimited by whitish walls and multiple dilated blood vessels that communicated with the cavitations. Histopathology revealed an increase in the number of vascular structures of variable calibre within loose fibrous connective tissue. The diagnosis of hepatic arteriovenous malformation was based on the lesions and confirmed by immunohistochemistry. Hepatic arteriovenous malformations are rare in all species, have not been described in cattle and should be included as a cause of mortality in neonates with post-partum haemoperitoneum.

Fetal Aorta-Portal Vein-Umbilical Vein Anastomosis: Prenatal Diagnosis and Brief Review of Literature

AbstractCongenital hepatic arteriovenous fistulae (AVFs) are rare and occur in less than 1:100,000 live births and are linked with poor perinatal outcome. Hepatic arteriovenous malformation can be of three types, out of which we present a case of hepatic AVF with AV connection in a case of primigravida at 26 weeks gestation presented with fetal growth restriction and Doppler changes.

Hepatic Arteriovenous Malformation in a Preterm Infant With High-Output Cardiac Failure

Congenital hepatic arteriovenous malformations (HAVM) are rare and serious with a known high mortality rate. They are mostly described in the term population and, if symptomatic, present with early-onset congestive heart failure. To our knowledge, there have been no published cases of an affected very preterm infant. Prenatal diagnosis and preprocedural planning are paramount in these critically ill infants. Strategies for management of HAVM differ depending on the size of both the infant and HAVM as well as severity of symptoms. Management may include supportive pharmacologic therapy, transcatheter embolization, and surgical resection or ligation. In this report, we present the case of a 28-week gestation infant with high-output cardiac failure secondary to prenatally diagnosed hepatic arteriovenous malformation. On day of life 3, the infant underwent successful transcatheter occlusion. However, despite maximal medical management and partial embolization of his HAVM, he did not survive.

Thrombosis in hereditary hemorrhagic telangiectasia

Thrombosis in hereditary hemorrhagic telangiectasia

Case Report of Hereditary Hemorrhagic Telangiectasia with Pulmonary and Hepatic Arteriovenous Malformations

Abstract Hereditary hemorrhagic telangiectasia (HHT) (Osler–Weber–Rendu syndrome) is a rare vascular disorder that usually presents with epistaxis, mucocutaneous telangiectasia, and gastrointestinal bleeding. Patients with pulmonary arteriovenous malformations (AVMs) are at serious risk of cerebral stroke due to paradoxical embolism, indicating the need for early diagnosis and intervention. We report a 24-year-old man who presented with hypoxemia and a history of recurrent spontaneous epistaxis, and radiologic workup demonstrating pulmonary and hepatic AVMs. He was diagnosed with HHT and treated by endovascular embolization.

A case of Rendu-Osler-Weber disease that presented with late-onset portosystemic encephalopathy due to hepatic arteriovenous malformations

A case of Rendu-Osler-Weber disease that presented with late-onset portosystemic encephalopathy due to hepatic arteriovenous malformations

Obstetrical and neonatal complications in hereditary haemorrhagic telangiectasia: A retrospective study.

To retrospectively describe a large series of pregnancies in women with hereditary haemorrhagic telangiectasia followed in our reference centre, plus neonatal outcomes, to better understand the risks of complications and to improve their prevention. A retrospective descriptive study conducted through a phone questionnaire. Reference centre for hereditary haemorrhagic telangiectasia in Lyon, France. Women meeting the following criteria: (1) alive and aged ≥18 years; (2) with a definite clinical and/or genetic diagnosis of hereditary haemorrhagic telangiectasia; and (3) with at least one full-term pregnancy. Maternal and perinatal outcomes of pregnancies in women with hereditary haemorrhagic telangiectasia. Five hundred and sixty-two pregnancies were reported in 207 women with hereditary haemorrhagic telangiectasia. A total of 271 complications (48.2%) were registered. Of these, 149 (55%) non-specific complications, 110 (40.6%) non-severe specific complications and 12 (4.4%) severe specific complications were registered. There were four cases of haemoptysis and two cases of transient ischaemic attack related to pulmonary arteriovenous malformations. Four patients had severe decompensated dyspnoea, related to pulmonary arteriovenous malformations in three cases and to pulmonary arteriovenous malformations associated with severe hepatic arteriovenous malformations in one case. Hepatobiliary necrosis occurred in one case. Epidural or spinal anaesthesia was performed in 139 of 452 deliveries (31%), without complications. There were 12 reports of congenital anomalies in 461 live births (3%). Most pregnancies in hereditary haemorrhagic telangiectasia women are uneventful; complications are rare but can be severe. Women thus need to be educated about screening and possible pregnancy-related risks before becoming pregnant.

Identifying racial disparities in hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by recurrent epistaxis (nose bleeds), mucosal telangiectasias (spider veins), and arteriovenous malformations. Although HHT affects all racial groups, few...

Hepatic Encephalopathy in Osler-Weber-Rendu Syndrome

Hereditary hemorrhagic telangiectasia or Osler-Weber-Rendu syndrome is a rare condition that leads to multiple vascular malformations. We describe the interesting patient case of a woman with recurrent epistaxis secondary to Osler-Weber-Rendu syndrome, who presented with confusion, and was ultimately found to have a hepatic arteriovenous malformation leading to hepatic encephalopathy. Computed tomography angiography images are provided, which highlight the extensive hepatic arterioportal shunting that caused elevated serum ammonia levels in the setting of gastrointestinal breakdown of blood products.

Cardiac and Hemodynamic Manifestations of Hereditary Hemorrhagic Telangiectasia.

The autosomal dominant trait hereditary hemorrhagic telangiectasia (HHT) causes multiorgan dysplastic lesions of the vasculature that can activate multiple physiological cascades leading to a broad array of cardiovascular diseases. Up to 78% of patients with HHT develop hepatic arteriovenous malformations (AVMs), which cause a hyperdynamic circulatory state secondary to hepatic/portal shunting. This condition can eventually progress to high-output cardiac failure (HOCF) with continued peripheral tissue hypoxemia. Treatment for HOCF is often limited to supportive measures (diuretics and treatment of anemia); however, recent studies using systemic bevacizumab have shown promise by substantially reducing the cardiac index. In the context of liver AVMs and high cardiac output, the pulmonary vasculature can also experience high flow. Without adequate dilation of pulmonary vessels, post-capillary pulmonary hypertension can develop. Another form of pulmonary hypertension observed in HHT, pulmonary arterial hypertension, is caused by HHT-related mutations in ENG and ACVRL1 causing congestive arteriopathy. Post-capillary pathogenesis is addressed by reducing the high-output state, whereas the pre-capillary state is treated with supportive mechanisms (diuretics, oxygen) and agents targeting pulmonary vasoreactivity: endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors. If either form of pulmonary hypertension is left untreated or proves refractory and progresses, the common hemodynamic complication is right heart failure. Targeted right heart therapies involve similar strategies to those of pulmonary arterial hypertension, with several experimental approaches under study. In this review, we describe in detail the mechanisms of pathogenesis, diagnosis, and treatment of the hemodynamic complications and associated cardiovascular diseases that may arise in patients with HHT.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

BackgroundHereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians.MethodsUsing DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review.ResultsIn total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively.ConclusionsIn a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Predictors of heart failure symptoms in hereditary hemorrhagic telangiectasia patients with hepatic arteriovenous malformations

BackgroundHepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms.Results176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared.In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372–4.754) and 0.489 (95% CI 0.299–0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816–0.996), sensitivity 80.0% (95% CI 55.7–93.4%), and specificity 75.0% (95% CI 52.9–89.4%).ConclusionsCTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.

S3173 Gastric Masson’s Hemangioma: A Rare Cause of Hematemesis

Introduction: Intravascular papillary endothelial hyperplasia (IPEH) or Masson’s Hemangioma (MH) is a rare, benign vascular tumor. It is most commonly reported to occur in the head, neck and hands. MH in the gastrointestinal (GI) tract is exceedingly uncommon, with no reported cases of gastric MH till date. We report a unique patient with gastric MH who presented with massive hematemesis. Case Description/Methods: A 41-year-old male presented to the hospital with several episodes of hematemesis with clots. His medical history was significant for pulmonary embolism status post IVC filter and hepatic arteriovenous malformation status post coil embolization. He denied alcohol abuse, retching or prior episodes of hematemesis. Patient was on aspirin 81 mg/day, but was not taking non steroidal anti inflammatory drugs or anti-coagulants. Vital signs were normal and physical assessment was unremarkable except for melena on the rectal exam. Subsequent esophagogastroduodenoscopy showed a 4x4 cm protuberant, ulcerated gastric submucosal mass on lesser curvature of distal body with overlying clot but no active bleeding (Fig. 1a). A follow up CT scan of the abdomen and pelvis showed a 4.0 x 3.3 x 3.6 cm mass in the lesser curvature of the gastric body which extended into the gastro-hepatic space (Fig. 1b). Patient developed recurrent hematemesis and was immediately taken for surgical resection. Exploratory laparotomy and wedge resection of actively bleeding 5 cm ulcerated gastric mass was performed (Fig. 1c). Histologically, the lesion showed a central area consisting of thrombotic material surrounded by a proliferation of papillary structures and hyperplastic endothelial cells. CD34 and Factor VIII stains were positive for endothelial cells and Elastic Van Gieson stain confirmed the lesion was within a large vessel. These findings were consistent with a diagnosis of Masson’s Hemangioma (Fig. 1d). Patient had an uneventful post-surgical course and was discharged with follow up in the surgery clinic. Discussion: Masson’s Hemangioma in the GI tract is an extremely rare entity which may lead to life threatening GI bleed. Lesions are reactive endothelial hyperplasia around a pre-existing thrombus, mostly associated with underlying prothrombotic states. It is important to rule out aggressive vascular lesions such as angiosarcoma, when considering the histologic diagnoses of MH. Surgical resection represents a definitive cure and is associated with an excellent prognosis.Figure 1.: A: Axial contrast-enhanced CT: Enlarged, heterogeneously-enhancing bilateral ovaries (arrows), representing infiltrating Krukenberg tumors. U, Uterus. A, Ascites. B: Axial contrast-enhanced CT: Enlarged periaortic and pericaval lymph nodes (arrows), suspicious for metastatic disease. A, Ascites. C:Sagittal contrast-enhanced CT: Irregular thickening with nodular enhancement of the gastric body (white arrows), as is seen with infiltrating malignancy. Reticulation and soft-tissue density of the omental fat (red arrows), representing omental caking.

Pulmonary Vascular Complications in Hereditary Hemorrhagic Telangiectasia and the Underlying Pathophysiology.

In this review, we discuss the role of transforming growth factor-beta (TGF-β) in the development of pulmonary vascular disease (PVD), both pulmonary arteriovenous malformations (AVM) and pulmonary hypertension (PH), in hereditary hemorrhagic telangiectasia (HHT). HHT or Rendu-Osler-Weber disease is an autosomal dominant genetic disorder with an estimated prevalence of 1 in 5000 persons and characterized by epistaxis, telangiectasia and AVMs in more than 80% of cases, HHT is caused by a mutation in the ENG gene on chromosome 9 encoding for the protein endoglin or activin receptor-like kinase 1 (ACVRL1) gene on chromosome 12 encoding for the protein ALK-1, resulting in HHT type 1 or HHT type 2, respectively. A third disease-causing mutation has been found in the SMAD-4 gene, causing a combination of HHT and juvenile polyposis coli. All three genes play a role in the TGF-β signaling pathway that is essential in angiogenesis where it plays a pivotal role in neoangiogenesis, vessel maturation and stabilization. PH is characterized by elevated mean pulmonary arterial pressure caused by a variety of different underlying pathologies. HHT carries an additional increased risk of PH because of high cardiac output as a result of anemia and shunting through hepatic AVMs, or development of pulmonary arterial hypertension due to interference of the TGF-β pathway. HHT in combination with PH is associated with a worse prognosis due to right-sided cardiac failure. The treatment of PVD in HHT includes medical or interventional therapy.