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Keywords:

  • Doppler ultrasonography;
  • hereditary hemorrhagic telangiectasia;
  • liver biopsy;
  • liver involvement;
  • liver transplantation;
  • vascular malformations

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

Abstract: Study Purpose: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process.

Consensus Process: A nominal group technique was used. A list of main clinical, diagnostic and therapeutic issues about liver involvement in HHT was generated by the organizing committee. Panel members then scored their agreement with each statement; the median score, and standard deviation for each statement were determined for each of the three successive panel rounds. These consensus statements formed the basis for recommendations graded with the strength and quality of supporting evidence.

Recommendation Statements: Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population. Liver biopsy in any patient with proven or suspected HHT should be avoided. Liver involvement in HHT is generally asymptomatic; in the minority of patients where it is symptomatic, morbidity and mortality can be substantial. The prevalence of focal nodular hyperplasia is much higher in patients with liver involvement by HHT than in the general population. Invasive therapies for liver involvement by HHT (namely liver transplantation) should be considered only in patients who have failed to respond to intensive medical therapy.

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).

Table 1.   Curaçao diagnostic criteria for HHT
Criteria
  1. HHT, hemorrhagic telangiectasia; VM, vascular malformation.

EpistaxisSpontaneous, recurrent nosebleeds
TelangiectasesMultiple at characteristic sites (lips, oral cavity, fingers, nose)
Visceral lesionsPulmonary VMs, liver VMs, cerebral VMs, spinal VMs, gastrointestinal telangiectases (with or without bleeding)
Family historyA first-degree relative with HHT according to these criteria
HHT diagnosis is
 DefiniteIf three criteria are present
 Possible/suspectedIf two criteria are present
 UnlikelyIf fewer than two criteria are present

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:

  • 1
    Is screening appropriate for liver involvement in HHT?
  • 2
    Is Doppler ultrasound sufficiently accurate and suitable for screening of liver involvement in HHT?
  • 3
    In a scale from 1 to 9 (from no impact to life-threatening), how should the clinical impact of liver involvement in HHT be rated?
  • 4
    How should the clinical importance of cholestasis in liver involvement in HHT be rated?
  • 5
    How should the clinical importance of focal nodular hyperplasia (FNH) in liver involvement in HHT be rated?
  • 6
    Is transarterial embolization an effective and safe option for symptomatic liver involvement? (with two ranks, for effectiveness and safety, respectively)
  • 7
    Is liver transplantation the only curative option for symptomatic liver involvement?
  • 8
    Can appropriate timing for liver transplantation be identified?

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.

Table 2.   Categorization of evidence and grading of recommendations
Description
Category and grade
IEvidence obtained from at least one randomized trial or meta-analysis
IIEvidence obtained from at least one controlled nonrandomized study
IIIEvidence obtained from well-designed descriptive studies
IVEvidence obtained from expert reports or opinions, or clinical experiences of respected authorities
Classification of recommendations
AThe group feels this point should be strongly recommended; or, there is a good evidence (not necessarily of grades I and II) to support the recommendation
BRecommendation rated moderately important by the group; or, there is a fair evidence to support the recommendation
CRated as relatively unimportant by the group, or not recommendable; or, there is a poor evidence to support the recommendation

Background

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

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

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

Diagnosis of liver involvement in HHT

Screening for liver involvement in HHT

Liver involvement in HHT can be investigated in three different settings:

  • A.
    Systematic evaluation, that is, liver evaluation (liver tests plus imaging) in all subjects at risk for HHT (CIII).
  • B.
    Research purpose evaluation, that is, liver evaluation in all subjects at risk for HHT in the context of a research program, i.e. to clarify different aspects of liver involvement (AIII).
  • C.
    Liver evaluation in the diagnosis of HHT in subjects with 1 or 2 Curaçao criteria, and in whom genetic testing is either inconclusive or unavailable (of note, genetic testing is not 100% accurate) (AIII).
Doppler ultrasound for screening of liver involvement in HHT

Doppler US is sufficiently accurate and suitable for first-line imaging of the liver in the general HHT population (AII).

Liver biopsy

Independent of the performance of testing to investigate the presence of liver involvement by HHT, liver biopsy in any patient with proven or suspected HHT should be avoided, particularly considering the reported high prevalence of liver VMs in HHT (32–74%) (AIV).

Clinical features of liver involvement in HHT

Clinical impact of liver involvement in HHT

Asymptomatic liver involvement is common, but in the minority of patients in whom it is symptomatic, the clinical significance is great as it is associated with significant morbidity and mortality (AIII).

Clinical importance of cholestasis in liver involvement in HHT

Asymptomatic abnormalities in biochemical markers of cholestasis (e.g. alkaline phosphatase, γ-glutamyl transpeptidase) are of little clinical significance (AIII).

Clinical importance of FNH in liver involvement in HHT

The clinical importance of FNH is low as this is a benign liver lesion (AII). However physicians caring for HHT patients should know that:

  • the prevalence of FNH is much higher in patients with liver involvement by HHT than in the general population and therefore clinicians should be made aware of this possibility so that unnecessary invasive work-up can be avoided (AIII);
  • characterization of FNH can be made non invasively by evaluating clinical and laboratory data (including serological tumor markers) and imaging (at least two examinations – whether Doppler sonography, MR, CT or liver scintigraphy – showing suggestive findings) (AII);
  • in the presence of a liver mass suggestive of FNH in a patient with HHT, biopsy and excision of the lesion should not be performed (AIII);
  • in patients with HHT and FNH who require estrogen/progesterone therapy, ultrasonographic follow-up should be performed and hormonal therapy discontinued in case of significant symptomatic tumor enlargement (AIV).

Treatment of symptomatic liver involvement

Invasive therapies for liver involvement by HHT should be considered only in patients who have failed to respond to intensive medical therapy. In the case of high-output heart failure, assessment and treatment by a cardiologist should be performed before considering an invasive therapy (AIV).

Transarterial embolization for symptomatic liver involvement

Transarterial embolization of liver VMs is a palliative, temporizing and high-risk procedure that may be used as a last resort in patients who are not candidates for liver transplantation (AIV).

Transarterial embolization of liver VMs should be absolutely avoided in patients with biliary symptoms/signs (AIII).

Liver transplantation for symptomatic liver involvement

Liver transplantation is indicated in patients with ischemic biliary necrosis, in those with intractable high-output cardiac failure or portal hypertension, with a different priority (urgent in biliary cases, lower priority for other cases) (AIV).

Note: Right heart catheterization should always be performed in patients with HHT being evaluated for liver transplantation (AIV). From experience drawn from patients with cirrhosis and portopulmonary hypertension, liver transplantation may be attempted in HHT patients with high output cardiac failure who have pulmonary vascular resistance <240 dynes s/cm5 and should be avoided in HHT patients who have true severe pulmonary hypertension (according to the local liver transplantation protocol) because of high perioperative mortality (>50%); other causes of pulmonary hypertension should be excluded (BIV). Limited data are, however, available on transplanting these patients; therefore, transplant should only be performed after conferring with a medical team with expertise in HHT.

Timing for liver transplantation

Except for the priorities mentioned above (urgent for biliary necrosis), there are currently no established criteria that allow the identification of the appropriate timing for liver transplantation (BIV).

Future studies

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

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.

Endorsements

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

Endorsed by the Scientific and Medical Advisory Board of the HHT Foundation International, by the HHT Foundation International which supported the 6th International HHT Conference in Lyon, and by the Mario Negri Institute for Pharmacological Research – Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Italy.

Appendix 1

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

Steps of consensus process

The organizing committee planned the preliminary steps: literature search, selection of panel of experts and discussants with a facilitator, drafting of issues to be addressed.

A systematic literature search was performed (MedLine, EMBASE, Cochrane Library, with search terms: telangiectasia, hereditary hemorrhagic, liver, liver diseases, arteriovenous malformations, liver vascular malformations, liver/hepatic involvement, involvement, liver transplant/transplantation; embolization, therapeutic; transarterial embolization) up to April 2005. A total of 159 relevant papers were found, mostly representing single case reports or small case series. Twelve out of 159 were series of patients including five patients or more and describing a total of 275 patients; nine out of these series were well-designed descriptive studies (III) and one was a nonrandomized-controlled clinical trial (II).

Twelve experts and nine discussants were selected in the context of teams/centers from Europe and North America dedicated to HHT care on the basis of their known expertise in HHT and particularly regarding liver involvement in HHT. They either had substantially contributed to the relevant literature or their varied multidisciplinary expertise was felt to be an asset to discussing the complex multidisciplinary management of liver involvement in HHT. As HHT patients are cared for in various medical contexts, care was also taken so that representatives of different health care systems were included in the panel. All but one of the selected experts and discussants agreed to participate in the consensus process.

Considering the high specialization level and dedication of all attendees at the International HHT Scientific Conference, it was decided to incorporate rankings coming from the final session audience in the statement.

The main issues to be addressed were drawn from the conclusions of the scientific session regarding liver involvement in HHT held during the 5th International HHT Scientific Conference in Bonaire, 2003, and from review of the relevant literature.

Consensus process occurred in rounds.

  • 1
    The first round of the nominal group was performed by e-mail before the Conference. The experts who at that stage were unaware of the panel composition to avoid dominance and interferences, ranked each proposed issue. During the first round, discussants also received issues for their personal consideration and preparation for plenary discussion. The facilitator then summarized the results of this first round by calculating a median score for each proposed issue with range of dispersion; the average standard deviation (SD) for this round was 1.7. The facilitator then provided to every expert the overall results of the first round, together with his/her initial rankings so as he/she could further consider them in relation to their colleagues' assessments. The facilitator also instructed experts and coopted discussants so as to ensure that all participants to discussions could express their views, particularly outliers and those with atypical opinions, and to keep their professional views and personal experience from dominating the discussion. During the first day of the Lyon conference, consensus background, aims and methodology were presented to the attendees. Issues and rankings were then presented, each one of them with relevant median score and range of vote dispersion, so that experts, discussants and conference participants could discuss. All comments and suggestions received were recorded by facilitator.
  • 2
    The second round of process occurred on conference day 2, when experts and discussants met to re-rank the issues, in view of suggestions received and new science presented at the conference, and to develop a proposal of consensus on this basis. The average SD of second round voting was 0.07.
  • 3
    During the third round on conference day 3, the consensus proposal was presented to the conference participants, who were then asked to discuss and vote on every issue. Proposed issues had an average 79.3% of agreement, 6.7% of partial agreement, 5.7% of disagreement, with an 8.3% of abstensions variously motivated. Consensus statements were further tuned based on this plenary discussion and voting.

Appendix 2

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References

Consensus panel

Organizing Committee: H. Plauchu (France), M. E. Faughnan (Canada), E. Buscarini (Italy).

Experts: E. Buscarini (Italy), M. E. Faughnan (Canada), G. Garcia Tsao (USA), G. Lesca (France), M. J. Marion (France), F. Miller (USA), J. P. Pelage (France), H. Plauchu (France), C. Sabbà (Italy), J. C. Saurin (France), R. White (USA).

Discussants: B. Bancel (France), O. Boillot (France), R. Brenard (Belgium), J. J. Mager (the Netherlands), D. Marion (France), K. Swanson (USA), C. J. Westermann (the Netherlands), L. Wu (Canada), L. Young (USA).

Facilitator: E. Buscarini (Italy).

Statistics: Perna Annalisa (Italy).

References

  1. Top of page
  2. Abstract
  3. Background
  4. Recommendation statements
  5. Future studies
  6. Endorsements
  7. Appendix 1
  8. Appendix 2
  9. References
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