Elsevier

Digestive and Liver Disease

Volume 37, Issue 9, September 2005, Pages 635-645
Digestive and Liver Disease

Review Article
Liver involvement in hereditary haemorrhagic telangiectasia or Rendu-Osler-Weber disease

https://doi.org/10.1016/j.dld.2005.04.010Get rights and content

Abstract

Hereditary haemorrhagic telangiectasia is a genetic disease characterised by the presence of teleangiectases virtually involving every organ. Hepatic involvement is represented by a spectrum of vascular abnormalities, which evolve in a continuum from tiny teleangiectases to substantial vascular malformations, potentially with a progressively greater arteriovenous shunt. Liver involvement in hereditary haemorrhagic telangiectasia is almost always asymptomatic; on the other hand, hepatic vascular malformations can induce severe complications, depending on the predominant venous side of the arteriovenous fistulas—high-output cardiac failure in the case of hepatohepatic fistulas, and portal hypertension in the case of hepatoportal fistulas. Doppler sonography can detect and stage hepatic vascular malformations in subjects with hereditary haemorrhagic telangiectasia; according to Doppler sonographic grading, appropriate advice for follow-up and/or therapy can be given.

Introduction

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is an autosomal dominant dysplasia characterised by widespread cutaneous, mucosal and visceral telangiectases with a frequency which has been estimated as one or two cases out of 10 000 subjects [1], [2]. Telangiectasia is the elementary lesion of HHT, arising from the dilatation of a post capillary venule which directly fuses with an arteriole, bypassing the capillary system. Clinical presentation in affected people varies greatly, depending on the number, type and location of telangiectases or vascular malformations (VMs) with potential morbidity and mortality; attempts have been made to establish internationally accepted clinical criteria for the diagnosis; these criteria, first proposed by Plauchu et al. [3], were recently revised by a panel of experts [4]. The search for visceral involvement in HHT can help to determine the affection status in terms of Curaçao criteria and is especially important for visceral VMs, such as lung, brain and liver VMs, which can cause life-threatening complications [4].

Section snippets

Genetics of HHT

Mutations in at least two different genes may lead to the clinical picture of HHT: the gene encoding for endoglin (ENG) is localised on chromosome 9q34 and is mutated in HHT type 1 [5] while the gene encoding activin receptor type II-like kinase I (ALK-1) is localised on chromosome 12q11-14 and is mutated in HHT type 2 [6].

ENG and ALK-1 are components of the transforming growth factor-β (TGF-β) pathway and are predominantly expressed on vascular endothelium. TGF-β belongs to the cytokines and

Pathogenesis of liver involvement

Liver involvement in HHT is defined by the presence of VMs potentially involving all hepatic vessels. At the earliest stage vascular derangement is represented by the microscopic telangiectases scattered throughout liver parenchyma and visible also on liver surface at laparoscopy or surgery [10] (Fig. 1). The evolution of vascular lesion is represented by progressive enlargement and creation of multiple direct arteriovenous communications [11]. A model derived by a three-dimensional analysis of

Clinical findings

Patients with liver VMs are generally asymptomatic. In a recent series [26], only four of 52 (8%) presented symptoms; in a larger series of 92 patients with liver involvement (out of a group of 222 patients with HHT), only eight (8.6%) were symptomatic [15]. Physical signs of large intrahepatic fistulas could be a vascular sound at hepatic auscultation and/or a thrill at palpation. Substantial liver enlargement can also be found, possibly associated with ascites and peripheral oedema.

Diagnosis

Liver VMs should be diagnosed in the context of a definition of HHT affection status according to the Curaçao criteria (Table 1) [4].

From a clinical point of view, hepatic VMs cannot be identified or even suspected, unless the presence of a drastically enlarged hepatic artery would cause the typical thrill/bruit. In some retrospective studies liver involvement was diagnosed on the basis of clinical criteria such as hepatomegaly or jaundice; however, this diagnosis is always equivocal as

Hepatic VMs: is screening advisable?

Many reasons support a screening policy for hepatic VMs in families with HHT.

First, hepatic VMs are likely to be found in at least one-third of the subjects with HHT. Second, even if hepatic involvement in HHT seems to be benign in most cases, as demonstrated in a first Doppler US screening report (with 3/13 symptomatic patients [20] as well as by the results of following studies (with 8% of symptomatic subjects) [15], [26], complications from liver VMs can be very severe, even life–threatening

Evaluation of systemic impact of liver involvement

Once a diagnosis of hepatic VMs has been established, the severity and type of the predominant intrahepatic shunt would determine what, if any, further testing is required. Whereas early stages (grades 0+, 1 and 2 of proposed classification) do not call for any other tests, periodical echocardiography is advised for grades 3 and 4 to evaluate cardiac function and overload as well as pulmonary artery pressure. For arterioportal shunts, upper gastrointestinal endoscopy should be scheduled to

Prevalence of hepatic involvement in HHT

The prevalence of hepatic involvement in HHT can be estimated correctly only by family screening using imaging techniques; by clinical criteria it was estimated with limited reliability by clinical criteria as 8% [49] to 31% [50]. In 1997, an imaging-based screening study of a large family (73 investigated subjects) showed hepatic VMs in 13 females among 40 affected patients (32.5% of affected subjects and 43.4% of the affected females) [20]. The same group [15] in a recent paper describing the

Natural history

So far no data are available in literature on natural history of liver VMs; this information can be best derived from family screening thus including the complete spectrum of hepatic VMs. In our series of 379 subjects screened for hepatic VMs from April 1992 to December 2004, 252 were affected by HHT. Ninety-eight of them showed hepatic VMs to the first observation, six during the follow-up, totalling 104 (41.2%) subjects with liver VMs; presently follow-up data are available for 69/104 with an

Therapeutic options

Although grades 0+, 1 and 2 do not require any therapy, grade 3 and, furthermore, grade 4 can entail symptoms and/or signs. Anicteric cholestasis is common in these patients and no therapy is necessary, but physician should be aware that life-threatening necrotising cholangitis can only be resolved by an emergency liver transplant [31].

Complications of portal hypertension (bleeding from gastro-oesophageal varices, ascites) should be treated with consolidated medical and endoscopic treatments.

Acknowledgements

Research and screening program on Italian HHT families is supported, in part, by a grant from the Fondazione Italiana HHT ‘Onilde Carini’. Authors wish to thank Mrs. Letizia Bottelli, in-charge of Library of Maggiore Hospital in Crema, for her dedication and support in the bibliographic search.

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