Hereditary hemorrhagic telangiectasia,liver vascular malformations and cardiac consequences

BackgroundHHT patients with liver vascular malformations (VMs) may develop high-output cardiac failure requiring liver transplant in few cases.ObjectiveOur aim is to show that echocardiography is a good tool to evaluate the severity of hepatic vascular malformations in HHT and can improve medical management in HHT patients.MethodsThe study is a cross-sectional study of cardiac parameters in HHT patients with dyspnea in a single referral center. All HHT patients with dyspnea, consecutively seen at HHT reference center in Lyon between May 2007 and November 2009 were included and had hepatic vascular Ultrasound and Echocardiography. Echocardiographic measures included cardiac output (CO) and index (CI), left ventricle (LV) filling pressures, and pulmonary artery pressure. Then, patients were classified in 4 groups according to the severity: group 1 (normal values), group 2 with isolated high CI, group 3 with high CI and increased LV-filling pressures and group 4 with increased LV-filling pressures and pulmonary hypertension.ResultsFifty-two HHT-patients were analyzed. Eight patients were in group 1, 25 in group 2, 6 in group 3 and 13 in group 4. Age, NYHA class dyspnea, edema, atrial fibrillation, hepatic artery diameter, and BNP (brain natriuretic peptide) levels significantly increased from groups 1 to 4 as well as left atrial area, and presence of mitral regurgitation. Patients with associated pulmonary VMs (n = 11) did not show any clinical or echocardiographic differences.ConclusionPerforming echocardiography in HHT patients with dyspnea allowed us to better understand the physiological processes of high-CO failure complicating liver vascular malformations and may improve follow-up of patients and treatment decisions.     

Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life-threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT.     

Pulmonary hypertension in hereditary haemorrhagic telangiectasia

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain, liver and lungs. Pulmonary hypertension (PH) is increasingly recognised as a severe complication of HHT. PH may be categorised into two distinct types in patients with HHT. Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations. Less frequently, the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension. Differentiation between both forms of PH by right heart catheterisation is essential, since both entities are associated with severe morbidity and mortality with different treatment options. Therefore all HHT patients should be referred to an HHT centre.     

Hereditary hemorrhagic telangiectasia: to transplant or not to transplant?

This report comments the case reported by Muller et al. which describes a combination of at least two different indications for orthotopic liver transplant (OLT) in a same patient: hepatocarcinoma and HHT complicated with severe liver involvement and high output cardiac failure. This case report highlighted that the clear time for OLT in HHT can be difficult to determine. In HHT, if intensive medical approach is not efficient, OLT, has to be considered. In the case of Muller et al., the patient was correctly listed for OLT for a single hepatocellular carcinoma, however, he did not receive a sufficient priority so as to avoid worsening of liver vascular malformations complications. Bevacizumab may be a therapeutic option in the treatment of complicated liver VMs in HHT, However, the recurrence of symptoms after withdrawal of the drug make it unsuitable as a replacement for OLT in the cure of complicated liver VMs in HHT. In the case reported by Muller et al. the right “OLT window” after bevacizumab was lost. The right time for OLT in severe complicated liver VMs in HHT does exist but, as this case illustrates, it can be very difficult to determine. As OLT is a radical cure for liver VMs, with excellent outcomes, it should be the therapeutic choice in patients under the age of 65 years. Bevacizumab may be an interesting option, either for patients over the age of 65 years, or those who are poor candidates for surgery; if these latter respond to bevacizumab they should be re‐ evaluated for OLT (with a “fast‐ track”) as the prognosis of severe complicated liver VMs is very poor.     

Hepatic vascular malformations in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that can involve the liver diffusely in the form of vascular malformations ranging from small telangiectases to discrete arteriovenous malformations. Anatomically, three different patterns of abnormal vascular communications can occur in liver: portal vein to hepatic vein (portovenous), hepatic artery to hepatic vein (arteriovenous) and hepatic artery to portal vein (arterioportal), with the most common being arteriovenous. Only 5 to 8% of patients with these vascular malformations are symptomatic. When symptomatic, patients present with high-output cardiac failure, biliary ischemia (which, when severe, can progress to biliary and hepatic necrosis and lead to acute liver failure), or portal hypertension. Other less common presentations include portosystemic encephalopathy and abdominal angina. Diagnosis is confirmed by Doppler ultrasonography or multidetector computed tomography. The hallmark findings are intrahepatic hypervascularization and an enlarged common hepatic artery. Focal nodular hyperplasia and nodular regenerative hyperplasia are common findings. Symptomatic patients are treated with intensive medical treatment aimed at the predominant clinical presentation. Patients who fail aggressive medical therapy and those with acute biliary/hepatic necrosis should be considered for liver transplantation.     

Liver involvement in hereditary hemorrhagic telangiectasia (HHT)

Liver involvement in hereditary hemorrhagic telangiectasia (HHT) consists of extensive intrahepatic vascular malformations associated with blood shunting (arteriovenous, arterioportal and/or portovenous). It is a rare disorder that nevertheless can result in significant systemic and hepatobiliary abnormalities. Although hepatic vascular malformations are present in a majority of patients with HHT, symptoms occur in a only a minority with a clear predominance for the female gender. Symptoms from liver vascular malformations are often misdiagnosed and this can lead to potentially harmful interventions. In this review article, clinical findings of liver involvement in HHT and their pathophysiology are discussed as well as diagnostic methodologies, therapies used and their outcome. Data presented is based on a review of the literature performed in October 2006 using the following MEDLINE search terms: (hereditary hemorrhagic telangiectasia [ALL] OR Rendu-Osler-Weber [ALL]) AND (liver OR hepatic [ALL]). Papers were considered if they were published in English and if they included specific cases that were sufficiently described.     

Hereditary hemorrhagic telangiectasia with multiple hepatic and pulmonary nodular lesions

A 50-year-old female visited the hospital for further evaluation of multiple pulmonary and hepatic nodules. First, she visited her primary physician for general fatigue due to anemia. She had recurrent epistaxis, and her mother had suffered from hereditary hemorrhagic telangiectasia (HHT). Telangiectasias were present in the stomach. This patient was diagnosed with HHT. Computed tomography (CT) revealed multiple pulmonary and hepatic nodules. The pulmonary nodules were due to bleeding from arteriovenous malformations of the lung. Abdominal CT and angiography showed a dilated and meandering hepatic artery, arteriovenous shunts and multiple hepatic nodules. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed enhancement in the early dynamic phase and in the liver-specific phase. A liver tumor biopsy of a hepatic nodule showed nodular regenerative hyperplasia (NRH). This report presents a case of HHT with multiple pulmonary and hepatic nodular lesions. Gd-EOB-DTPA-enhanced MRI was useful for making a diagnosis of NRH.     

Liver involvement in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease with an autosomal dominant inheritance pattern, characterized by widespread telangiectases that can involve the skin, mucous membranes, lung, brain, gastrointestinal tract and/or liver. It has an estimated prevalence of 1 to 2 cases per 10,000. The prevalence of hepatic involvement in HHT had been estimated in 8% to 31% in retrospective studies but in more recent large prospective series the prevalence is higher, ranging between 41% and 78%. Nevertheless, symptoms occur only in 8% of the patients with HHT and liver involvement. Liver involvement by HHT is characterized by widespread diffuse liver vascular malformations that give rise to three types of shunting: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal vein), and portovenous (portal vein to hepatic vein). The three most common initial clinical presentations are high-output heart failure, portal hypertension and biliary disease. We describe the case of a patient with diagnosis of HHT and hepatic involvement and we review of the literature. A 58-year-old woman with HHT came to consultation with heart failure symptoms and echographic and endoscopic findings of portal hypertension. The multislice computed tomography of the abdomen revealed the presence of multiple telangiectases in the hepatic parenchyma and a shunt from the hepatic artery to the portal vein. We conclude that the symptomatic involvement of the liver in HHT is an extremely infrequent entity. It must be suspected when clinical manifestations and compatible imagenologic findings exist in patients with antecedents of HHT.     

Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and its manifestation in the liver

M. Osler (Hereditary Hemorrhagic Telangiectasia, HHT) is an autosomal dominant inherited disease, with various vascular malformations. The genetic cause of this disease lies in different defects of transmembrane proteins (endoglin, activin receptor like-kinase 1) that can be defined as components of the receptor complex for transforming growth factor beta (TGF beta). Vascular malformations include the gastrointestinal tract and especially the liver. The location of mutations encoding hepatic involvement of M. Osler still remains unknown. These vascular malformations may lead to different shunts in the liver and can result to different complications like cardiac-insufficiency, portal hypertension and hepatic encephalopathy in adulthood. Color Doppler sonography is the method of choice for screening patients with M. Osler--suspected of having hepatic involvement. As in rare events conservative treatment of complications of hepatic involvement fail, embolization of the hepatic artery as minimal invasive therapy, surgical ligation of the A. hepatica and liver transplantation are possible treatment options. As there are only limited experiences with these therapeutic procedures patients with liver involvement should be treated at a center, where all therapy options are available.     

Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary haemorrhagic telangiectasia (Weber-Rendu-Osler disease)

Background—Arteriovenous malformations of theliver in Osler's disease may present as high output cardiac failure. Afew case reports suggested that treatment with arterial embolisationmay have beneficial effects in such patients.
Aims—To investigate the efficacy and safety ofthis treatment modality in a prospective pilot study.
Patients and methods—Four women and one man (aged39-59 years) with the dominant hepatic manifestation of Osler'sdisease presented with symptoms of cardiac failure and elevated cardiac output. Arteriovenous malformations were treated in three to five sessions with arterial embolisation using coils. The outcome was analysed by measurement of cardiac output and scoring of clinical symptoms.
Results—Embolisation was technically feasible inall patients and adequate occlusion of vascular malformations wasachieved in four patients. After completion of therapy symptomsimproved in four patients, while one patient suffered from abdominalpain due to cholangitis. One patient died seven months after theembolisation treatment from variceal bleeding. Mean cardiac outputsignificantly decreased from 14.2 (range 12-17.3) l/min to 8 (range5.9-10.6) l/min (p=0.043). After a median follow up of 23 months(range 7-50 months), three of five patients had a long lastingimprovement of clinical symptoms and cardiac function.
Conclusions—This first treatment series ofpatients with dominant hepatic involvement in Osler's diseaseindicates that arterial embolisation may prevent cardiac failure bysignificantly lowering cardiac output.

Keywords:hereditary haemorrhagic telangiectasia; Weber-Rendu-Osler disease; hepatic vascular malformation; cardiacfailure; embolisation therapy

     

Evaluation of previously nonscreened hereditary hemorrhagic telangiectasia patients shows frequent liver involvement and early cardiac consequences

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by cutaneous, mucosal, and sometimes visceral arteriovenous malformations. Severe hepatic manifestations have been characterized in a subgroup of patients, but few data are available in previously nonscreened patients. We prospectively evaluated liver involvement and its cardiac consequences in such patients. Between 2000 and 2005, we prospectively evaluated the clinical, biological, and hepatic Doppler sonography (DS) characteristics of 102 consecutive HHT patients (mean age, 52.5 years; range, 19-88; 80.4%) with an identified genetic mutation. Patients were segregated into three different severity groups according to DS values. Factors predictive of an abnormal DS, according to predetermined criteria, and of a high cardiac index were identified by logistic and linear regression analysis, respectively. Abnormal liver biology and clinical signs of hepatic involvement were present in 35.3% and 27.5% of cases, respectively. Abnormal DS (defined as at least enlargement of the main hepatic artery) was observed in 56 (54.9%) cases, and direct or indirect signs of significant fistulas were present in 26 (25.5%) cases. Abnormal liver biology and a mutation involving the ACVRL1 gene were predictive of hepatic ultrasound (US) abnormalities. The diameter of the main hepatic artery and the presence of focal nodular hyperplasia (FNH) were predictive of a higher cardiac index. CONCLUSION: This large prospective series of previously nonscreened HHT patients identified a subgroup at risk of liver involvement (patients with abnormal liver biology and ACVRL1 mutations) and a subgroup with a higher cardiac index: future studies will show whether such patients would benefit from systematic DS screening and long-term cardiac surveillance.     

The liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease)

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT, Osler disease) is an inborn error in the structure of different vessels. This leads to vascular malformations in multiple organ systems. In the liver vascular abnormalities are associated with a marked fibrosis and/or cirrhosis. METHODS AND RESULTS: We found hepatic manifestation of Osler disease in four women and one man (51-63 years old) presenting initially with slight disturbances of liver function. In three patients progressive liver insufficiency developed. The characteristic histologic and sonographic findings are described and discussed. CONCLUSION: Ultrasonography with color and Doppler analysis is diagnostic, replacing more extensive procedures like angiography, computer tomography, or magnetic resonance tomography.     

Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT)

Hepatic involvement in hereditary hemorrhagic telangiectasia (HHT) is highly variable and may lead to severe clinical symptoms such as heart failure. This controlled, prospective study defined sonographic criteria for hepatic involvement in HHT. Color Doppler sonography and pulsed Doppler sonography were used to study 25 patients with HHT and liver involvement, 20 patients with HHT without liver involvement, 25 patients with cirrhosis, and 25 patients without liver disease. The diagnosis of hepatic manifestation was confirmed by computed tomography and/or angiography. Liver size, parenchymal changes of the liver, vessel diameters, and flow velocities of the portal vein and the hepatic artery were determined. Resistance index (RI) and pulsatility index (PI) were calculated. The diameter of the common hepatic artery was significantly dilated without overlap between HHT patients with liver involvement and the 3 control groups (mean 11.3 +/- 2.8 mm [HHT with liver involvement], 4.6 +/- 0.9 mm [HHT without liver involvement], 4.8 +/- 1.0 mm [cirrhosis], and 4.4 +/- 1.0 mm [healthy controls], P <.001). Doppler parameters of the proper hepatic artery differed significantly (all P <.001). In all patients with HHT and liver involvement, areas with intrahepatic hypervascularization caused by dilated intrahepatic arteries were observed in varying intensity. Cardiac output significantly correlated with the diameter of the common hepatic artery (r = 0.53, P =.007) and the portal vein (r = 0.42, P =.05). In conclusion, the diameter of the common hepatic artery (>7 mm) and intrahepatic hypervascularization are suitable sonographic diagnostic parameters of HHT with high sensitivity and specificity. Dilated diameters of the hepatic feeding vessels are indicators for systemic circulatory distress in these patients.     

Intrahepatic Osler's disease: report of two cases and review of the literature

Osler-Weber-Rendu disease is a hereditary vascular disease with multiple manifestations. The liver is involved rarely. Vascular abnormalities include telangiectasis and arteriovenous fistulas, sometimes associated with fibrosis and cirrhosis. Hepatic arteriovenous shunting may include secondary portal hypertension, reduced liver function and high cardiac output. Two cases of Osler-Weber-Rendu disease with extensive hepatic arteriovenous fistulation were described in detail and we report on their clinical features. In the first patient, treatment was symptomatic since liver transplantation is not indicated because the patient was asymptomatic. Embolization treatment of hepatic arteries was indicated in the second patient because he had biliary disease and recurrent cholangitis secondary to vasculo-biliary shunts. Therapy with arterial embolization, banding, or ligature of hepatic arteries is still limited and provides unsatisfactory long-term results. Liver transplantation offers now another therapeutic option for patients with intrahepatic high shunting and secondary pulmonary hypertension.     

Successful bosentan therapy for pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is a hereditary vascular disease with multiple arterial venous malformations. Pulmonary arterial hypertension is occasionally associated with HHT; however, there is no evidence of targeted therapy for this subgroup of patients. This report describes a 37-year-old woman who presented with dyspnea on exertion. She was finally diagnosed with pulmonary arterial hypertension associated with HHT (HHT2, MIM 600376), and had multiple arterial venous malformations in the lung, liver and pancreas. An oral dual endothelin receptor (ET_A/ET_B) antagonist, bosentan, was prescribed, and her symptoms, exercise capacity and laboratory findings imporved greatly after treatment. Pulmonary arterial pressure also decreased. Endothelin receptor antagonist is a possible treatment option for pulmonary arterial hypertension associated with HHT.     

Liver disease in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an hereditary disorder that results in fibrovascular dysplasia with the development of telangiectasias and arteriovenous malformations. It predominantly involves the skin, mucous membranes, viscera, lungs, and brain. Hereditary hemorrhagic telangiectasia shows great genetic heterogeneity, and its phenotypes have been classified based on the recently identified mutated genes: endoglin (HHT-1) and activin-like kinase receptor-1 (HHT-2). Other families with phenotypic HHT do not bear these mutations; therefore, other genes are probably involved as well. Liver involvement is reported in up to 30% of persons affected by HHT. Large arteriovenous malformations in the liver can lead to significant complications, including high-output congestive heart failure, portal hypertension, hepatic encephalopathy, biliary ischemia, and liver failure. Embolization of large arteriovenous malformations in the liver remains controversial; however, liver transplantation can successfully eradicate these complications.     

A case of pulmonary arteriovenous fistula associated with multiple hepatic arterioportal shunts]

We report a case of pulmonary arteriovenous fistula with multiple hepatic arterioportal shunts. A 23-year-old man was admitted for evaluation of a nodular shadow in the right lower lung field. Chest CT showed a homogeneous and well-defined nodular shadow in the right S7. 3-dimensional CT revealed an arteriovenous fistula composed of a feeding artery and a draining vein in the right S7. Abdominal enhanced CT revealed a diffusely heterogeneous pattern in the liver parenchyma and the portal vein staining diffusely at the late arterial phase. We diagnosed pulmonary arteriovenous fistula associated with multiple hepatic arterioportal shunts. Pulmonary arteriovenous fistula is often associated with hereditary hemorrhagic telangiectasia (HHT). This case did not meet the criteria for HHT at this time. However, we could not exclude the possibility of HHT because clinical manifestations of HHT become apparent after 40 years old among 10% of patients. The natural history and treatment of HHT are not clear. We concluded that we should be careful to detect possible manifestations as HHT when we diagnose and follow up patients with pulmonary arteriovenous fistula.     

Non‐transplant surgical approach to liver‐based hereditary haemorrhagic telangiectasia: a first report

A 55‐year‐old woman with hereditary haemorrhagic telangiectasia (HHT) underwent a left lateral liver bisegmentectomy (removal of segments 2 and 3) for hepatic‐based arteriovenous malformations. This lesion determined a progressive fatigue and invalidating effort dyspnoea. The postoperative course was uneventful and the patient is currently doing well at 4 years after surgery. To our knowledge, this is the first case of hepatic‐based HHT treated with liver resection. This anecdotal report should promote the evaluation of this approach in order to define its role in the treatment of liver involvement in this rare disease.     

Hypertension portale et maladie de Rendu-Osler-Weber familiale

Background

Rendu-Osler-Weber disease is an autosomal dominant disease, characterized by widespread telangiectasia that can affect the skin, mucous membranes and many organs. The prevalence of liver involvement in patients with Rendu-Osler-Weber disease classically ranges from 8 to 31%, caused by vascular malformations which can be complicated by portal hypertension.

Case report

M. N.Z, a 40-year-old patient with familial and personal hemorrhagic antecedents was hospitalised in 2003 for severe anaemia. The clinical examination found telangiectases in skin and mucous membranes, hepatomegaly, splenomegaly, oedema and ascites. Abdominal sonography showed a homogeneous hepatosplenomegaly, ascites and an enlarged common hepatic artery. Doppler ultrasonography showed the presence of shunting between hepatic artery and portal vein. The ascites was rivalta negative. The upper digestive endoscopy showed stage II oesophageal varices and D1 telangiectasia. The patient received propranolol 160 mg/l and a diuretic. The patient developed refractory ascites and anaemia which required puncture, albuminotherapy and blood transfusions. The patient died six months later.

Discussion and conclusion

Hepatic vascular malformations in Rendu-Osler-Weber disease are generally asymptomatic. However, portal hypertension, as in our case, or severe biliary complications are possible. Doppler ultrasonography enables a diagnosis to be made. Liver transplant is the definitive treatment in cases of cardiac failure, biliary necrosis and/or portal hypertension.