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Hereditary Hemorrhagic Telangiectasia

Time Not Only to Recognize the Disease but Also to Prioritize the Symptomatic Patient on the Waiting List

Lerut, Jan p. MD, PhD1

doi: 10.1097/TP.0000000000002492

1 Université catholique Louvain UCL, Brussels, Belgium.

Received 1 October 2018.

Accepted 5 October 2018.

The author declares no funding or conflict of interest.

Correspondence: Jan Lerut, MD, PhD, Université catholique de Louvain (UCL), Av. Hippocrate 10 1200, Brussels, Belgium. (

In this issue, Lyer et al report on the US liver transplantation (LT) experience in hereditary hemorrhagic telangiectasia (HHT) patients based on data from 39 patients collected by the Scientific Registry of Transplant Recipients between 1998 and 2016.1 Five patients from the Mayo Clinic (Rochester, MN) had detailed pre- and posttransplant investigations. Twenty-four were in younger patients (median age of 47.5 y) with a low calculated Model for End-Stage Liver Disease score (median value, 8.0) and 75% received an exceptional Model for End-Stage Liver Disease score. Two (8.3%) status 1 patients died during transplant surgery, but the long-term results were excellent, with 86% long-term survival. The 4 Mayo Clinic patients transplanted because of high-output cardiac failure (HOCF) reversed this condition.1

The disease was originally described in 1865 by Babington2 but is better known under the three-fold eponym, Rendu-Osler-Weber disease. Henri Rendu differentiated this disease in 1896 from hemophilia in a patient with severe nose bleedings, William Osler documented the hereditary trait of the disease in 1901, and finally Frederick Weber refined the clinical description in a patient series in 1907.2-5 HHT, or Rendu-Osler-Weber disease, is a hereditary autosomal dominant disease that affects mainly skin and mucosa but can also be present in the brain, lung, digestive tract, and liver. Five mutations leading to dysplastic modifications in the endothelium have been documented. More than 90% of mutations affect the formation of endoglin and activin-like receptor kinase, both proteins involved in the repair of blood vessels. These mutations result in HHT types 1 and 2; this distinction is important because HHT1 families more frequently display pulmonary arteriovenous malformations (AVM), and HHT2 families have a milder and later-onset disease but a higher incidence of liver involvement.

The diagnosis of HHT is based on the criteria defined in 1999 at Curaçao, which include nose bleeding, cutaneous and mucosal telangiectasia, visceral telangiectasia and AVMs, and a familial history. Three or 4 criteria secure the diagnosis.6

The disease is symptomatic in 15% of patients. Using modern imaging techniques, liver involvement has been shown to be present in up to 78% of patients. Depending on the shunt type, hepatic-based HHT presents either as cardiac failure and biliary disease (arteriovenous shunt) or portal hypertension (arterioportal shunt). The hyperdynamic state can lead to lead to HOCF as well as portal hypertension with the development of massive fluid shifts and ascites. Intrahepatic shunts frequently cause massive biliary necrosis and sepsis. Hepatic involvement is therefore often synonymous with a life-threatening condition.7

As the indications for LT became clearly defined through the 1960s to 1990s, vascular liver diseases, whether benign (such as HHT) or malignant (such as hemangioendothelioma), largely escaped the attention of the transplant and hepatology community. Perhaps this can be explained by their rarity, with HHT having a prevalence of only 2 in 10000, as well as their protean clinical and morphologic manifestation. The scarce worldwide experience began with Pichlmayr in Hannover who performed the first LT for hepatic-based HHT in 1985, but poor experiences and the fact that HHT interfered with clear therapeutic allocation algorithms led to endless discussions about prioritization on the waiting list even with life-threatening complications, such as HOCF and repetitive biliary sepsis, are present. However, because LT permits a complete cure and recovery by eliminating the responsible AVM, the situation changed with the 2006 publication of the European Liver Intestine Transplant Association–European Liver Transplant Registry (ELTR) series of 40 recipients including detailed pre- and post-LT data and excellent 10-year survival rates of 82.5% despite the presence of cardiac failure and ongoing sepsis due to biliary necrosis in nearly all patients.8

The large European study contained 3 very important messages. First, it was documented that overt cardiac failure (and even presence of secondary pulmonary arterial hypertension) can be reversed rapidly after transplantation; second, treatment of major pulmonary and splanchnic AVM using interventional radiologic procedures before LT is mandatory to reduce post-LT morbidity and mortality; and finally, excellent short-term as well as long-term results could be achieved. These data sparked the interest of the transplant and hepatology community for the treatment of hepatic-based HHT8 as shown by the increased use of LT over time, from 40 LTs between 1985 and 2003 compared with 34 LTs in half the time between 2006 and 2016 in Europe (personal communication ELTR). This European experience was also reflected in the United States, with 5 patients transplanted from 1998 to 2005 and 34 from 2006 to 2016.1 Recently, it has been reported that antiangiogenic medications can improve these conditions, but to date, these therapies have not been shown to be capable of reversing, and thus curing, hepatic-based HHT.9

Italian observations as well as the European Liver Intestine Transplant Association–ELTR report revealed that the disease can recur in the allograft.8,10,11 The Lyon group also recently reported, based on repetitive imaging and pathology including immunostaining to demonstrate replacement of vascular endothelium by recipient cells, a recurrence risk of over 40% at 15 years (personal communication, Dumortier and Boillot).

The interesting HHT US report clearly shows that LT needs to be considered not only more frequently but also more rapidly in HHT patients, especially those presenting the life threatening biliary and cardiac complications as well as those with development of severe portal hypertension. Based on both the European and now the US experiences these usually young patients need to be prioritized on the waiting list when they present with life-threatening complications of hepatic HHT. Such a strategy could easily be justified by detailed investigation to provide objective evidence of cardiopulmonary function, degree of portal hypertension, and evidence of biliary necrosis and sepsis.

Recurrent allograft disease indicates that life-long follow-up including repetitive imaging and pathology, perhaps including documentation of microchimerism of the endothelial lining, are mandatory.

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