Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations

Hereditary hemorrhagic telangiectasia (HHT), or Rendu–Osler–Weber disease, is a genetic disease characterized by cutaneous and mucosal telangiectases and visceral vascular malformations (VMs) with an estimated prevalence of one to two cases per 10 000 (1, 2). The telangiectasia is the characteristic lesion of HHT, and consists of a direct connection between the arteriole and venule without intervening capillary. Clinical presentation varies greatly, depending on the number, type and location of telangiectases and larger VMs. Genetic testing has recently become available, although its sensitivity is yet to be determined. The clinical diagnostic criteria for HHT (Curaçao criteria) are outlined in Table 1 (3).

Visceral VMs, in particular pulmonary, cerebral and hepatic VMs, can lead to debilitating and life-threatening complications but are frequently asymptomatic. Screening for visceral involvement in HHT can help to confirm diagnosis of HHT based on Curaçao criteria in some cases. Whereas it has been recommended that HHT patients be screened for pulmonary VMs, as these can be treated presymptomatically to prevent life-threatening complications (4–7), the role of screening for liver VMs remains less well defined.

Scientists interested in the study of HHT have been meeting biannually since 1996 at an International HHT Scientific Conference, which has the objective of fostering collaboration and sharing information among basic and clinical scientists. The HHT scientific and clinical community is highly interested in developing consensus practice guidelines for HHT care. Although evidence-based practice guidelines exist for a number of common disorders, consensus regarding clinical practice is particularly valuable in rare diseases, as health providers face the challenge of making clinical decisions in situations where there can be a limited evidence base in the medical literature. Where published information is inadequate or nonexistent, consensus methods can be useful to synthesize the insights of experts to guide decision-making.

During the 6th HHT International Scientific Conference held in Lyon in 2005, a session was specially dedicated to develop consensus on a selected topic in HHT: liver involvement. An established consensus method, the nominal group technique, also known as expert panel, was selected (8). The aims of the consensus session were as follows: (1) to determine the extent to which experts in this field agree about given issues (consensus measurement), and potentially, (2) to develop a consensus statement on fundamental clinical, diagnostic and therapeutic issues about liver involvement in HHT.

The main issues to be addressed were as follows:

A detailed description of the consensus process and results of each round (see Appendix 1) were recorded and evaluated by statistics experts. This short version of the consensus summarizes the main conclusions and recommendations from the conference. Recommendation statements were graded for their strength and quality using the grading system shown in Table 2.

Background

Liver involvement in HHT is defined by a spectrum of VMs that can involve the liver diffusely and evolve in a continuum from small telangiectases to large arteriovenous malformations (9). Three different and often concurrent types of intrahepatic shunting can be observed: hepatic artery to hepatic veins, hepatic artery to portal vein and portal vein to hepatic vein (10–12), leading potentially to high-output cardiac failure (with symptoms of exertional dyspnea, ascites and edema), portal hypertension (leading to variceal hemorrhage and ascites), biliary ischemia or encephalopathy (13). Abnormal vessels may be surrounded by fibrous tissue, leading to expansion of the portal areas or focally septal fibrosis but without the formation of complete regenerative nodules as in cirrhosis (14). Of note, VMs shunting may lead to abnormalities in liver parenchyma and the biliary tree. Livers with HHT may show hepatocellular regenerative activity (15), either diffuse or partial, leading to nodular regenerative hyperplasia or FNH, respectively. In fact, it has recently been reported that the prevalence of FNH in patients with HHT is 100-fold greater than in the general population (16). The combination of fibrosis (around abnormal vessels), nodular regenerative hyperplasia and portal hypertension may lead to a misdiagnosis of cirrhosis. However, this is not true cirrhosis (and has been called “pseudocirrhosis”) and it is not associated with liver insufficiency (14, 17). Portal hypertension in HHT is due to hepatic artery to portal vein shunting and/or to nodular regenerative hyperplasia. Reported cases of true cirrhosis in HHT patients may have been the result of multiple blood transfusions and the development of chronic viral hepatitis (before the establishment of routine screening of blood donors for hepatitis markers) (14).

As bile duct blood supply is derived entirely from the hepatic artery, arteriovenous shunting can lead to bile duct ischemia resulting in chronic bile duct damage and cholestasis, mostly resulting in increases in alkaline phosphatase and γ-glutamyl transpeptidase values of about 3 up to 10 times normal values (14, 17). Rarely bile duct ischemia can ominously lead to bile duct necrosis and cholangitis, a catastrophic complication that has been termed “hepatic disintegration” (18).

The diagnosis of liver involvement by HHT nowadays can be made by sensitive imaging methods such as abdominal Doppler sonography (US) (10, 11, 19) or abdominal computed tomography (CT) (12, 20). The diagnosis of liver involvement in HHT requires laboratory assessment and imaging: Doppler US has been proposed as a screening technique taking into account its accuracy for the detection and grading of liver VMs, its noninvasiveness, availability, repeatability and low cost (17, 19, 21). To date, however, only a few centers perform systematic screening of HHT families for liver VMs. Further testing (either one or a combination of the following: CT, magnetic resonance, scintigraphy, angiography, echocardiography, cardiac catheterization) may be required depending either on the presence of focal liver lesions or on the severity of liver involvement and its hemodynamic impact (16, 22).

Hepatic involvement in HHT affected subjects has been estimated to be between 32.5% and 72.7% using Doppler US (21, 23), and between 67% and 74% using multislice CT (12, 20), implying a prevalence varying between one case per 7000 to one per 30 000. Patient selection and genotypic regional variation likely account for some of this variability.

So far, there are little available data regarding the natural history of liver involvement in HHT. Liver synthetic function is generally well preserved (13, 17) (anecdotally, liver failure caused by substantial replacement of hepatic parenchyma by vascular malformations has been reported (24)). In two larger series of patients (totaling 144 patients) with liver involvement, only 8% were symptomatic (12, 21).

No treatment is currently recommended for patients with asymptomatic liver involvement by HHT.

In patients with symptomatic liver involvement, management depends on the type of complication. High-output heart failure, the most common complication, responds in its majority to intensive medical therapy (including correction of anemia, salt restriction and diuretics, antihypertensive agents, antiarrhytmic agents, digoxin, as clinically indicated) (13). Complications of portal hypertension (bleeding from gastroesophageal varices, ascites) should be treated as recommended in cirrhotic patients (13). Notably, limited experience with the transjugular intrahepatic portosystemic shunt indicates that it may not be helpful in the setting of liver involvement by HHT, while it will increase shunting and worsen the hyperdynamic circulatory state (13, 25). Cholangitis due to bile duct ischemia is treated with antibiotics (whereas there is apparently no role for biliary stenting), although this complication has a poor prognosis.

For any patient with complicated liver VMs failing to respond to treatment and exhibiting a progressive worsening of their clinical condition, invasive palliative treatments have been proposed. Transarterial embolization of liver arteriovenous fistulas has been so far applied in 33 patients with the main indication of high-output cardiac failure (26–28); four fatal outcomes were, however, reported with significant complications in the postembolization survivors, suggesting caution in its use (29–31).

Orthotopic liver transplantation has been proposed as the only definitive curative option for hepatic VMs in HHT. The main indications considered for liver transplantation to date have been high output cardiac failure, biliary necrosis and portal hypertension. In 23 reported cases, postoperative mortality was about 10%; in most patients, the long-term results were favorable (32–35).

Recommendation statements

Future studies

Available data on liver involvement in HHT remain limited. During the conference, a number of potential areas for future research were identified, particularly concerning clinical presentation of liver involvement in HHT, natural history and outcomes of treatments for liver VMs.

Appendix 1

Appendix 2