Hepatic Vascular Malformations in Hereditary Hemorrhagic Telangiectasia

ABSTRACT

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that can involve the liver diffusely in the form of vascular malformations ranging from small telangiectases to discrete arteriovenous malformations. Anatomically, three different patterns of abnormal vascular communications can occur in liver: portal vein to hepatic vein (portovenous), hepatic artery to hepatic vein (arteriovenous) and hepatic artery to portal vein (arterioportal), with the most common being arteriovenous. Only 5 to 8% of patients with these vascular malformations are symptomatic. When symptomatic, patients present with high-output cardiac failure, biliary ischemia (which, when severe, can progress to biliary and hepatic necrosis and lead to acute liver failure), or portal hypertension. Other less common presentations include portosystemic encephalopathy and abdominal angina. Diagnosis is confirmed by Doppler ultrasonography or multidetector computed tomography. The hallmark findings are intrahepatic hypervascularization and an enlarged common hepatic artery. Focal nodular hyperplasia and nodular regenerative hyperplasia are common findings. Symptomatic patients are treated with intensive medical treatment aimed at the predominant clinical presentation. Patients who fail aggressive medical therapy and those with acute biliary/hepatic necrosis should be considered for liver transplantation.

Liver vascular malformations - hepatic vascular malformations - hereditary hemorrhagic telangiectasia - Rendu–Osler–Weber disease

REFERENCES

• 1 Plauchu H, DeChadarevian J P, Bideau A et al.. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.  Am J Med Genet. 1989;  32 291-297
• 2 Dakeishi M, Shioya T, Wada Y et al.. Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.  Hum Mutat. 2002;  19 140-148
• 3 Kjeldsen A D, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients.  J Intern Med. 1999;  245 31-39
• 4 Braverman I M, Keh A, Jacobson B S. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia.  J Invest Dermatol. 1990;  95 422-427
• 5 Guttmacher A E, Marchuk D A, White R I. Hereditary hemorrhagic telangiectasia.  N Engl J Med. 1995;  333 918-924
• 6 Shovlin C L, Guttmacher A E, Buscarini E et al.. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).  Am J Med Genet. 2000;  91 66-67
• 7 McAllister K A, Grogg K M, Johnson D W et al.. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.  Nat Genet. 1994;  8 345-351
• 8 Johnson D W, Berg J N, Baldwin M A et al.. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2.  Nat Genet. 1996;  13 189-195
• 9 McDonald M T, Papenberg K A, Ghosh S et al.. A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33–34.  Nat Genet. 1994;  6 197-204
• 10 Shovlin C L, Hughes J M, Tuddenham E G et al.. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3.  Nat Genet. 1994;  6 205-209
• 11 Johnson D W, Berg J N, Gallione C J et al.. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12.  Genome Res. 1995;  5 21-28
• 12 Vincent P, Plauchu H, Hazan J et al.. A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q.  Hum Mol Genet. 1995;  4 945-949
• 13 Cole S G, Begbie M E, Wallace G M et al.. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.  J Med Genet. 2005;  42 577-582
• 14 Bayrak-Toydemir P, McDonald J, Akarsu N et al.. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7.  Am J Med Genet A. 2006;  140 2155-2162
• 15 Gallione C J, Repetto G M, Legius E et al.. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).  Lancet. 2004;  363 852-859
• 16 Berg J, Porteous M, Reinhardt D et al.. Hereditary haemorrhagic telangiectasia: a questionnaire based study to delineate the different phenotypes caused by endoglin and ALK1 mutations.  J Med Genet. 2003;  40 585-590
• 17 Bayrak-Toydemir P, McDonald J, Markewitz B et al.. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations.  Am J Med Genet A. 2006;  140 463-470
• 18 Lesca G, Olivieri C, Burnichon N et al.. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.  Genet Med. 2007;  9 14-22
• 19 Letteboer T G, Mager H J, Snijder R J et al.. Genotype-phenotype relationship in hereditary hemorrhagic telangiectasia.  J Med Genet. 2006;  43 371-377
• 20 Sabba C, Pasculli G, Lenato G M et al.. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers.  J Thromb Haemost. 2007;  5 1149-1157
• 21 Cloft H J. Spontaneous regression of cerebral arteriovenous malformation in hereditary hemorrhagic telangiectasia.  AJNR Am J Neuroradiol. 2002;  23 1049-1050
• 22 Leung K M, Agid R, terBrugge K. Spontaneous regression of a cerebral arteriovenous malformation in a child with hereditary hemorrhagic telangiectasia. Case report.  J Neurosurg. 2006;  105 428-431
• 23 Du R, Hashimoto T, Tihan T et al.. Growth and regression of arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia. Case report.  J Neurosurg. 2007;  106 470-477
• 24 Hashimoto M, Tate E, Nishii T et al.. Angiography of hepatic vascular malformations associated with hereditary hemorrhagic telangiectasia.  Cardiovasc Intervent Radiol. 2003;  26 177-180
• 25 Wheatley-Price P, Shovlin C, Chao D. Interferon for metastatic renal cell cancer causing regression of hereditary hemorrhagic telangiectasia.  J Clin Gastroenterol. 2005;  39 344-345
• 26 Massoud O I, Youssef W I, Mullen K D. Resolution of hereditary hemorrhagic telangiectasia and anemia with prolonged alpha-interferon therapy for chronic hepatitis C.  J Clin Gastroenterol. 2004;  38 377-379
• 27 Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab.  Ann Hematol. 2006;  85 631-632
• 28 Mitchell A, Adams L A, MacQuillan G et al.. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia.  Liver Transpl. 2008;  14 210-213
• 29 Wanless I R, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia.  Arch Pathol Lab Med. 1986;  110 331-335
• 30 Sawabe M, Arai T, Esaki Y et al.. Three-dimensional organization of the hepatic microvasculature in hereditary hemorrhagic telangiectasia.  Arch Pathol Lab Med. 2001;  125 1219-1223
• 31 Siddiki H, Doherty M G, Fletcher J G et al.. Abdominal findings in hereditary hemorrhagic telangiectasia: pictorial essay on 2D and 3D findings with isotropic multiphase CT.  Radiographics. 2008;  28 171-184
• 32 Buscarini E, Danesino C, Olivieri C et al.. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia–results of extensive screening.  Ultraschall Med. 2004;  25 348-355
• 33 Ianora A A, Memeo M, Sabba C et al.. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement.  Radiology. 2004;  230 250-259
• 34 Memeo M, Stabile Ianora A A, Scardapane A et al.. Hepatic involvement in hereditary hemorrhagic telangiectasia: CT findings.  Abdom Imaging. 2004;  29 211-220
• 35 Buonamico P, Suppressa P, Lenato G M et al.. Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: Echo-color-Doppler vs multislice computed tomography study.  J Hepatol. 2008;  48(5) 811-820
• 36 Garcia-Tsao G, Korzenik J R, Young L et al.. Liver disease in patients with hereditary hemorrhagic telangiectasia.  N Engl J Med. 2000;  343 931-936
• 37 Caselitz M, Bahr M J, Bleck J S et al.. Sonographic criteria for the diagnosis of hepatic involvement in hereditary hemorrhagic telangiectasia (HHT).  Hepatology. 2003;  37 1139-1146
• 38 Ravard G, Soyer P, Boudiaf M et al.. Hepatic involvement in hereditary hemorrhagic telangiectasia: helical computed tomography features in 24 consecutive patients.  J Comput Assist Tomogr. 2004;  28 488-495
• 39 Wu J S, Saluja S, Garcia-Tsao G et al.. Liver involvement in hereditary hemorrhagic telangiectasia: CT and clinical findings do not correlate in symptomatic patients.  AJR Am J Roentgenol. 2006;  187 W399–405
• 40 Milot L, Gautier G, Beuf O et al.. Hereditary hemorrhagic telangiectases: magnetic resonance imaging features in liver involvement.  J Comput Assist Tomogr. 2006;  30 405-411
• 41 Buscarini E, Gebel M, Ocran K et al.. Interobserver agreement in diagnosing liver involvement in hereditary hemorrhagic telangiectasia by Doppler ultrasound.  Ultrasound Med Biol. 2008;  34(5) 718-725
• 42 Buscarini E, Plauchu H, Garcia-Tsao G et al.. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.  Liver Int. 2006;  26 1040-1046
• 43 Buscarini E, Danesino C, Plauchu H et al.. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.  Ultrasound Med Biol. 2004;  30 1089-1097
• 44 Wanless I R, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver.  Hepatology. 1985;  5 1194-1200
• 45 Bioulac-Sage P, Laumonier H, Cubel G et al.. Over-expression of glutamine synthase in focal nodular hyperplasia (part 1): early stages in the formation support the hypothesis of a focal hyper-arterialisation with venous (portal and hepatic) and biliary damage.  Comp Hepatol. 2008;  7 2
• 46 Martini G A. The liver in hereditary haemorrhagic teleangiectasia: an inborn error of vascular structure with multiple manifestations: a reappraisal.  Gut. 1978;  19 531-537
• 47 Cooney T, Sweeney E C, Coll R et al.. “Pseudocirrhosis” in hereditary hemorrhagic telangiectasia.  J Clin Pathol. 1977;  30 1134-1141
• 48 Buscarini E, Buscarini L, Danesino C et al.. Hepatic vascular malformations in hereditary hemorrhagic telangiectasia: Doppler sonographic screening in a large family.  J Hepatol. 1997;  26 111-118
• 49 Garcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiectasia (HHT).  J Hepatol. 2007;  46 499-507
• 50 Livneh A, Langevitz P, Morag B et al.. Functionally reversible hepatic arteriovenous fistulas during pregnancy in patients with hereditary hemorrhagic telangiectasia.  South Med J. 1988;  81 1047-1049
• 51 Khalid S K, Perschbacher J, Makan M, Barzilai B, Goodenberger D. Increased nose bleeding heralds high output cardiac failure in hereditary hemorrhagic telangiectasia – results of a case control study.  Hematology Meeting Reports. 2007;  1 23 , (abstract)
• 52 Khalid S K, Perschbacher J, Makan M, Goodenberger D, Barzilai B. Quantitative echocardiographic features of high output cardiac failure associated with hereditary hemorrhagic telangiectasia (HHT): A retrospective analysis.  J Am Soc Echocardiogr. 2007;  20 625A , (abstract)
• 53 Trembath R C, Thomson J R, Machado R D et al.. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia.  N Engl J Med. 2001;  345 325-334
• 54 Gothlin J H, Nordgard K, Janssen K et al.. Hepatic telangiectasia in Osler's disease treated with arterial embolization.  Eur J Radiol. 1982;  2 27-30
• 55 Brohee D, Franken P, Fievez M et al.. High-output right ventricular failure secondary to hepatic arteriovenous microfistulae. Selective arterial embolization treatment.  Arch Intern Med. 1984;  144 1282-1284
• 56 Derauf B J, Hunter D W, Sirr S A et al.. Peripheral embolization of diffuse hepatic arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia.  Cardiovasc Intervent Radiol. 1987;  10 80-83
• 57 Nikolopoulos N, Xynos E, Vassilakis J S. Familial occurrence of hyperdynamic circulation status due to intrahepatic fistulae in hereditary hemorrhagic telangiectasia.  Hepatogastroenterology. 1988;  35 167-168
• 58 Bourgeois N, Delcour C, Deviere J et al.. Osler-Weber-Rendu disease associated with hepatic involvement and high output heart failure.  J Clin Gastroenterol. 1990;  12 236-237
• 59 Whiting J H, Morton K A, Datz F L et al.. Embolization of hepatic arteriovenous malformations using radiolabeled and nonradiolabeled polyvinyl alcohol sponge in a patient with hereditary hemorrhagic telangiectasia: case report.  J Nucl Med. 1992;  33 260-262
• 60 Caselitz M, Wagner S, Chavan A et al.. Clinical outcome of transfemoral embolisation in patients with arteriovenous malformations of the liver in hereditary hemorrhagic telangiectasia (Weber-Rendu-Osler disease).  Gut. 1998;  42 123-126
• 61 Trotter J F, Suhocki P V, Lina J R et al.. Hereditary hemorrhagic telangiectasia causing high output cardiac failure: treatment with transcatheter embolization.  Am J Gastroenterol. 1998;  93 1569-1571
• 62 Stockx L, Raat H, Caerts B et al.. Transcatheter embolization of hepatic arteriovenous fistulas in Rendu-Osler-Weber disease: a case report and review of the literature.  Eur Radiol. 1999;  9 1434-1437
• 63 Hisamatsu K, Ueeda M, Ando M et al.. Peripheral arterial coil embolization for hepatic arteriovenous malformation in Osler-Weber-Rendu disease; useful for controlling high output heart failure, but harmful to the liver.  Intern Med. 1999;  38 962-968
• 64 Pfitzmann R, Heise M, Langrehr J M et al.. Liver transplantation for treatment of intrahepatic Osler's disease: first experiences.  Transplantation. 2001;  72 237-241
• 65 Thevenot T, Vanlemmens C, Di Martino V et al.. Liver transplantation for cardiac failure in patients with hereditary hemorrhagic telangiectasia.  Liver Transpl. 2005;  11 834-838
• 66 Radtke W E, Smith H C, Fulton R E et al.. Misdiagnosis of atrial septal defect in patients with hereditary telangiectasia (Osler-Weber-Rendu disease) and hepatic arteriovenous fistulas.  Am Heart J. 1978;  95 235-242
• 67 Neumann U P, Knoop M, Langrehr J M et al.. Effective therapy for hepatic M. Osler with systemic hypercirculation by ligation of the hepatic artery and subsequent liver transplantation.  Transpl Int. 1998;  11 323-326
• 68 Willinek W A, Hadizadeh D, von Falkenhausen M et al.. Magnetic resonance (MR) imaging and MR angiography for evaluation and follow-up of hepatic artery banding in patients with hepatic involvement of hereditary hemorrhagic telangiectasia.  Abdom Imaging. 2006;  31(6) 694-700
• 69 Koscielny A, Willinek W A, Hirner A et al.. Treatment of high output cardiac failure by flow-adapted hepatic artery banding (FHAB) in patients with hereditary hemorrhagic telangiectasia.  J Gastrointest Surg. 2007;  12(5) 872-876
• 70 Lerut J, Orlando G, Adam R et al.. liver transplantation for hereditary hemorrhagic telangiectasia: report of the European Liver Transplant Registry.  Ann Surg. 2006;  244 854-864
• 71 Peck-Radosavljevic M, Zacher J, Meng Y G et al.. Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver?.  J Hepatol. 1997;  27 127-131
• 72 Garcia-Tsao G, Sanyal A J, Grace N D et al.. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis.  Hepatology. 2007;  46 922-938
• 73 Runyon B A. Management of adult patients with ascites due to cirrhosis.  Hepatology. 2004;  39 841-856
• 74 Lee J Y, Korzenik J R, DeMasi R et al.. Transjugular intrahepatic portosystemic shunts in patients with hereditary hemorrhagic telangiectasia: failure to palliate gastrointestinal bleeding.  J Vasc Interv Radiol. 1998;  9 994-997
• 75 Chanson N, Carbonell N, Andreani T et al.. TIPS in hereditary hemorrhagic telangiectasia: never say never.  J Hepatol. 2008;  48 373-374
• 76 Zentler-Munro P L, Howard E R, Karani J, Williams R. Variceal hemorrhage in hereditary haemorrhagic telangiectasia.  Gut. 1989;  30 1293-1297
• 77 Ludwig J, Kim C H, Wiesner R H et al.. Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.  Hepatology. 1989;  9 215-218
• 78 Zajko A B, Campbell W L, Logsdon G A et al.. Cholangiographic findings in hepatic artery occlusion after liver transplantation.  AJR Am J Roentgenol. 1987;  149 485-489
• 79 Bauer T, Britton P, Lomas D et al.. Liver transplantation for hepatic arteriovenous malformation in hereditary hemorrhagic telangiectasia.  J Hepatol. 1995;  22 586-590
• 80 McInroy B, Zajko A B, Pinna A D. Biliary necrosis due to hepatic involvement with hereditary hemorrhagic telangiectasia.  AJR Am J Roentgenol. 1998;  170 413-415
• 81 Boillot O, Bianco F, Viale J-P et al.. Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement.  Gastroenterology. 1999;  116 187-192
• 82 Hillert C, Broering D C, Gundlach M et al.. Hepatic involvement in hereditary hemorrhagic telangiectasia: an unusual indication for liver transplantation.  Liver Transpl. 2001;  7 266-268
• 83 Blewitt R W, Brown C M, Wyatt J I. The pathology of acute hepatic disintegration in hereditary haemorrhagic telangiectasia.  Histopathology. 2003;  42 265-269
• 84 Lin E, Stall L. Spectrum of biliary abnormalities in hepatic hereditary hemorrhagic telangiectasia: demonstration by multidetector computed tomography.  Emerg Radiol. 2007;  14 461-463
• 85 Ferenci P, Lockwood A, Mullen K et al.. Hepatic encephalopathy - definition, nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998.  Hepatology. 2002;  35 716-721
• 86 Baba Y, Ohkubo K, Hamada K et al.. Hyperintense basal ganglia lesions on T1-weighted images in hereditary hemorrhagic telangiectasia with hepatic involvement.  J Comput Assist Tomogr. 1998;  22 976-979
• 87 Kobayashi Z, Tani Y, Watabiki S et al.. Brain MRI of hereditary hemorrhagic telangiectasia (HHT) with intrahepatic arteriovenous shunts.  Intern Med. 2005;  44 773-774
• 88 Yoshikawa K, Matsumoto M, Hamanaka M et al.. A case of manganese induced parkinsonism in hereditary haemorrhagic telangiectasia.  J Neurol Neurosurg Psychiatry. 2003;  74 1312-1314
• 89 Odorico J S, Hakim M N, Becker Y T et al.. Liver transplantation as definitive therapy for complications after arterial embolization for hepatic manifestations of hereditary hemorrhagic telangiectasia.  Liver Transpl Surg. 1998;  4 483-490
• 90 Chavan A, Caselitz M, Gratz K F et al. Hepatic artery embolization for treatment of patients with hereditary hemorrhagic telangiectasia and symptomatic hepatic vascular malformations.  Eur Radiol. 2004;  14 2079-2085
• 91 Garcia-Tsao G, Gish R G, Punch J. Model for end-stage liver disease (MELD) Exception for hereditary hemorrhagic telangiectasia.  Liver Transpl. 2006;  12(suppl 3) S108-S109