EASL Clinical Practice Guidelines

Hepatic vascular malformations in hereditary haemorrhagic telangiectasia

Definition

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber disease, is a genetic disorder with autosomal dominant inheritance, characterized by widespread cutaneous, mucosal and visceral telangiectasias and is reported to affect 1–2/10,000 people in the general population [133]. The clinical presentation of HHT varies widely based on the number, type and location of the telangiectasias or larger vascular malformations (VMs). The clinical criteria for HHT diagnosis, known as the Curaçao criteria, have been established by a panel of experts (Table 4): the diagnosis of HHT is certain with three criteria, likely with two, and unlikely with one or no criteria [134]. Most patients have mutations in one of the two known disease-related genes: endoglin (ENG, on chromosome 9, HHT1) and activin A receptor type II-like 1 (ACVRL1, on chromosome 12, HHT2), both of which are involved in the TGFβ pathway. Mutations in the SMAD4 gene can cause a rare syndrome combining juvenile polyposis and HHT; recently additional genes have been found on chromosome 5 and 7 [133]. Genetic testing is available on a clinical basis.

Table 4
Diagnostic criteria of HHT – Doppler ultrasound grading of liver VMs.


Hepatic VMs in HHT

Hepatic VMs are found in 44–74% of HHT-affected subjects [[135], [136]], implying a prevalence in the general (non-HHT) population varying between 1/7000 to 1/12,500. The prevalence of hepatic VMs depends substantially on HHT genotype, with greater frequency of hepatic VMs in HHT2 genotype than in HHT1 genotype [[137], [138]]. The penetrance of most of the clinical features of HHT depends on the patient’s age, with a mean age of patients with hepatic VMs of 52 years [139]. Previous data shows a strong and significant predominance of hepatic VMs in females who have HHT, both for asymptomatic and symptomatic lesions, with a male/female ratio varying from 1:2 to 1:4.5; therefore, the expression of HHT in the liver is likely dependent on the patient’s sex [[135], [137]].

Pathogenesis

Hepatic VMs unique to HHT involve the liver diffusely and evolve in a continuum from small telangiectases to large arteriovenous malformations, 21% of patients show an increased size of liver VMs and complexity over a median follow-up of 44 months [135].

Three different and often concomitant types of intrahepatic shunting (hepatic artery to portal vein, hepatic artery to hepatic vein and/or portal vein to hepatic vein) can lead to different but possibly coexistent clinical features: high-output cardiac failure (HOCF), PH, encephalopathy, biliary ischemia, and mesenteric ischemia, the latter two being due to a blood flow steal through arteriovenous shunting. Perfusion abnormality can also entail hepatocellular regenerative activity, either diffuse or partial, leading to focal nodular hyperplasia (FNH), which has a 100-fold greater prevalence in HHT patients than in the general population, or to nodular regenerative hyperplasia [[140], [141], [142], [143]].

Clinical presentations

Only 8% of patients with liver VMs are symptomatic in cross-sectional surveys [[136], [139]]. A recent cohort study with a median follow-up of 44 months has shown that hepatic VM-related morbidity and mortality will occur in 25% and 5% of patients respectively, with incidence rates of complications and death 3.6 and 1.1 per 100 person-years, respectively. The clinical outcome of liver VMs correlates with their severity [135].

HOCF represents the predominant complication associated with HHT [[142], [143]], but complicated PH occurs at a rate comparable to that of HOCF (1.4 and 1.2 respectively per 100 person-years); HOCF and complicated PH each accounts for about a half of hepatic VM–associated fatalities. In patients with chronic cardiac overload due to liver VMs atrial fibrillation occurred at a 1.6 rate per 100 person-years, suggesting that this arrhythmia in patients with liver VMs is not purely coincidental and should be approached with special caution [135].

PH due to arterioportal shunts can manifest itself with severe recurrent variceal bleeding; however both a case series and a cohort study have shown that gastrointestinal bleedings in patients with liver VMs were more often due to bleeding from gastrointestinal telangiectasias than to variceal bleeding [[135], [140]].

Anicteric cholestasis is observed in one-third of patients with liver VMs [135]; its degree is generally correlated with the severity of vascular malformations.

Much rarer presentations of liver VMs in HHT are encephalopathy, mesenteric angina, or ischemic cholangiopathy with potential hepatic necrosis [[135], [140], [142], [143], [144], [145]].

Diagnosis

Screening for hepatic VMs with Doppler ultrasound in asymptomatic individuals with suspected or certain HHT has been recommended because a correct diagnosis can help to clarify the diagnosis of HHT and improve subsequent patient management [[142], [143]].

The diagnosis of liver involvement in HHT requires laboratory assessment and sensitive imaging methods such as abdominal Doppler ultrasound or abdominal CT [[136], [139]]. Doppler ultrasound has been proposed as the first line investigation for the assessment of liver VMs taking into account its safety, tolerability, low costs, accuracy for the detection of liver VMs [[139], [146]] and good interobserver reproducibility [147]. Furthermore, Doppler ultrasound is the only imaging technique which can give a severity grading (from 0.5 to 4) (Table 4) of liver VMs which correlates with clinical outcome and allows a tailored patient management and follow-up [135].

Echocardiographic evaluation of cardiac function and morphology, particularly cardiac index and systolic pulmonary arterial pressure, gives a non-invasive estimate of the haemodynamic impact of liver VMs [148].

Further testing (either one or a combination of the following: gastrointestinal endoscopy, CT, MR, angiography, cardiac catheterisation, portal pressure measurement with hepatic venous pressure gradient) may be required depending either on the presence of focal liver lesions or on the severity of liver VMs and their haemodynamic impact.

Characterization of a liver mass in the context of HHT can be made non-invasively by evaluating epidemiological (and namely the high prevalence of FNH in HHT), clinical and laboratory data (including serological tumor markers, hepatitis B and C markers) as well as imaging (at least two examinations – whether Doppler ultrasound, MR or CT – showing suggestive findings). Liver biopsy is thus not necessary and should be regarded as risky in any patient with proven or suspected HHT, considering the reported high prevalence of liver VMs in HHT [[142], [143]].

Diffuse liver VMs are unique to HHT and their presence should always lead to the search of HHT diagnostic criteria. Other much rarer syndromes, such as Klippel-Trénaunay-Weber syndrome, can be associated to liver VMs. Multiple FNH, or, to a lesser extent, hypervascular metastases can cause enlargement of hepatic artery. The association of history, clinical and imaging findings together with the absence of other criteria for HHT will assist the correct diagnosis.

Treatment

Currently, no treatment is recommended for asymptomatic liver VMs. Patients with symptomatic liver VMs require intensive medical treatment either for HOCF (salt restriction, diuretics, beta blockers, digoxin, angiotensin-converting enzyme inhibitors, antiarrhythmic agents, cardioversion and radiofrequency catheter ablation), or for complications of PH and encephalopathy (as recommended in cirrhotic patients), or for cholangitis (antibiotics) [[142], [143]]. Supportive care is also important in these patients, either as blood transfusions or iron administration for anemia and treatment of the source of bleeding (either epistaxis or gastrointestinal bleeding) in actively bleeding patients.

Of note, 63% of patients show a complete response, and a further 21% a partial response to therapy for complicated liver VMs [135]. This high response rate argues for the importance of an intensive approach to symptomatic liver VMs and for a cautious approach to major remedies.

For patients failing to respond to an initial intensive medical therapy, invasive treatments, including transarterial embolization of liver VMs or OLT, are considered. There is sparse literature which suggests that the response to intensive treatments should be judged within 6 to 12 months [135].

Peripheral, staged embolization of liver VMs seems the most effective and repeatable transarterial treatment [149]. HOCF has been the main indication in these treated patients. However, a significant morbidity and 10% of fatal complications, together with its palliative role suggest caution in its use, which can be proposed only in severely symptomatic liver VMs not amenable to transplant [[142], [143]].

OLT represents the only definitive curative option for hepatic VMs in HHT, and is indicated for ischemic biliary necrosis, intractable HOCF and complicated PH [[142], [143]]. Post-operative mortality of OLT in HHT is 7–10%, with a long-term survival ranging between 82 and 92% [[144], [145]].

Right heart catheterisation should always be performed in patients with HHT being evaluated for OLT, to exclude severe pulmonary hypertension: OLT may be allowed in HHT patients with pulmonary vascular resistance <240 dynes sec cm−5 [142].

Bevacizumab, an angiogenesis inhibitor, has shown the ability to reduce the cardiac index in 24 patients with severe liver VMs and high cardiac output, with complete and partial response in 12% and 70%, respectively [150]. However, critical issues need to be carefully weighed regarding the use of bevacizumab; namely its unpredictable efficacy and non-negligible toxicity, revascularization following drug withdrawal, and problems with respects to angiogenesis-dependent phenomena such as wound and anastomoses healing, which could be critical in patients requiring emergency OLT.

The subset of patients with severe grade 4 liver VMs, at high risk of poor outcome, could be the target for prophylactic treatments. In the case of cardiac overload, angiotensin-converting enzyme inhibitors or carvedilol could be used to prevent cardiac remodeling, while for PH, beta blockers could be proposed to prevent gastrointestinal bleeding either from varices or from gastrointestinal telangiectasias [135].