SUBMITTED 2 AUG 22 1 REVISION REQ. 25 OCT 22; REVISION RECD. 18 DEC 22 2 ACCEPTED 17 JAN 23 3 ONLINE-FIRST: FEBRUARY 2023 4 DOI: https://doi.org/10.18295/squmj.1.2023.011 5 6 Hepatic Vascular Variants in Hereditary Haemorrhagic Telangiectasia 7 Imaging findings 8 *Alamelu Alagappan,1 Biswajit Sahoo,1 Jain H. Prakash,2 Manas K. 9 Panigrahi,2 Taraprasad Tripathy1 10 11 Departments of 1Radiodiagnosis and 2Gastroenterology, All India institute of medical sciences, 12 Bhubaneswar, Odisha, India. 13 *Corresponding Author’s e-mail: sornavallialagappan@gmail.com 14 15 Abstract 16 Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized 17 by vascular dysplasia. Hepatic Vascular Malformations (VMs) range from small telangiectases to 18 significant vascular shunting. Here we report two cases of HHT. Case 1 had diffuse ectasia of the 19 hepatic artery along its intrahepatic and extrahepatic course with a hepatic arterial aneurysm. 20 Case 2 presented with ileal and hepatic telangiectases. Knowledge of these vascular variants is 21 indispensable for clinicians and radiologists in aiding diagnosis and surgical and interventional 22 management. 23 Keywords: Vascular Malformations, HHT, Arteriovenous Malformation, Ileal Telangiectasis. 24 25 Introduction 26 Hereditary Haemorrhagic Telangiectasia (HHT), also known as Osler Weber Rendu syndrome, is 27 a multi-system autosomal dominant vascular disorder, with an incidence of one in 5000 to 8000 28 individuals.1 It was initially recognized as a mucocutaneous vascular disorder presenting with 29 epistaxis, gastrointestinal haemorrhage, and iron deficiency anaemia. However, with the 30 increasing use of imaging modalities, many patients come to attention with incidentally detected 31 visceral Vascular Malformations (VMs). Recent studies have demonstrated the frequent 32 occurrence of pulmonary, hepatic and cerebral vascular malformations, with an estimate that at 33 least 30% of HHT has hepatic involvement.2,3 With such high prevalence, it is fundamental for 34 all radiologists, physicians and hepatologists to be acquainted with hepatic vascular involvement 35 in HHT. Gastric and small bowel telangiectases are rare manifestations of HHT, most commonly 36 involving the stomach, duodenum and jejunum. The ileum is less commonly affected.4 This case 37 report presents two cases of HHT with hepatic vascular variants and one with ileal 38 telangiectases. 39 40 Case reports 41 Case One 42 A 35-year-old gentleman presented with a complaint of recurrent epistaxis for many years. He 43 had a vague upper abdominal discomfort for 2 years for which he underwent a screening 44 ultrasound abdomen which revealed the presence of hepatic arterio-portal shunting. On detailed 45 physical examination, there were multiple small reddish-purple lesions over both ear lobes, 46 fingertips and multiple oral telangiectases (Figure 1a, 1b). In presence of epistaxis with multiple 47 mucocutaneous telangiectases, the possibility of Hereditary Hemorrhagic Telangiectasia (HHT) 48 was considered. However, there was no family member affected by HHT. 49 50 After a preliminary examination, he was referred to the Radiodiagnosis department for dedicated 51 Ultrasonography (USG) and Contrast-Enhanced Computer Tomography (CECT) abdomen scan. 52 53 On USG, multiple dilated and tortuous vessels were seen in the liver, which showed arterial 54 waveform with peak systolic velocity in the range of 140 to 155cm/s. The portal vein, hepatic 55 vein, and inferior vena cava were usual with typical waveform. The liver showed normal 56 echotexture with smooth margins. (Figure 1c, 1d) 57 58 Triple phase CECT scan was acquired with arterial, portal, and venous phases after bolus 59 injection of contrast. On CECT arterial phase (Figure 2), variant hepatic arterial anatomy was 60 seen, with the left hepatic artery arising directly from the coeliac axis and common hepatic artery 61 arising from the coeliac axis giving rise to the middle hepatic artery and gastroduodenal artery 62 (GDA). The right hepatic artery was seen arising from the superior mesenteric artery (SMA). All 63 three hepatic arteries were tortuous and dilated (~12 mm) throughout their intrahepatic and 64 extrahepatic course. GDA, left gastric artery and splenic artery were normal in course and 65 calibre. The coeliac artery and SMA were dilated. An intrahepatic saccular aneurysm was seen 66 from a branch of the left hepatic artery. The portal vein and all three hepatic veins showed 67 normal contrast uptake. There was opacification of the peripheral portal branches in the arterial 68 phase, consistent with the presence of arterioportal shunting. Cranial magnetic resonance 69 imaging and Computed Tomography (CT) of the chest were normal. 70 71 These dilated and tortuous patterns of hepatic arteries with high peak systolic velocities led to 72 radiological suspicion of HHT. Based on Curaçao criteria [Table 1],2 a diagnosis of HHT was 73 established. 74 75 Case Two 76 A 56-year-old gentleman with HHT who had been followed up for 3 years got admitted owing to 77 multiple episodes of blood in his stools, primarily dark red. There was no history of fever, loose 78 stools, abdominal pain, or distension. His vitals were stable on admission (Pulse rate – 70 bpm, 79 Blood Pressure – 120/70 mmHg, Temperature – 99F, SpO2 – 98% in room air). Per Rectal 80 examination was unremarkable. Haemoglobin profile showed moderate anaemia (9 g/dL), with 81 normocytic normochromic anaemia. On CECT enterography (Figure 3), multiple arterial-82 enhancing ileal lesions were seen. Incidental multiple arterial enhancing lesions were also found 83 in the liver. On enteroscopy, the stomach and proximal small bowel appeared unremarkable. 84 Multiple blood clots were evident within the bowel loops with coffee brown-coloured fluid. 85 Multiple punctate lesions with pulsatile bleeding were seen in the terminal ileum (type 2A – 86 Yano Yamamoto classification),5 confirming the radiological diagnosis (Figure 3c). 87 88 Written consent was obtained from both patients for publication purposes. 89 90 91 92 Discussion 93 HHT is an autosomal dominant disorder characterized by vascular malformations. Nearly 80% of 94 HHT patients have identifiable mutations, most commonly ENG (endoglin, HHT1 genotype), 95 ACVRL1 (Activin A, HHT2 genotype) and MADH4 mutations.6 These causative genes are 96 involved in the TGF-β/BMP cell signalling pathway, which has a role in vascular 97 remodelling.7 Mutations in these genes lead to altered TGF-β/BMP signalling pathways 98 disrupting the endothelial response, smooth muscle differentiation, and vascular integrity 99 resulting in small, fragile vessels.8 100 101 Diagnosis of HHT is based on four criteria - recurrent epistaxis, mucocutaneous telangiectases, 102 visceral vascular lesions and an affected first-degree relative (The Curaçao criteria) [Table 1].2 103 According to these criteria, diagnosis of HHT is “definite” when three criteria are satisfied and 104 “possible” when two criteria are present. Vascular manifestations in HHT include telangiectasis, 105 aneurysms, and shunting. Common visceral vascular lesions include vascular malformations in 106 gastrointestinal, pulmonary, hepatic and central nervous system circulation. 107 108 Most hepatic vascular malformations in HHT are asymptomatic, with less than 10% of patients 109 having symptoms related to these lesions. Clinical manifestations are related to either high-110 output heart failure or portal hypertension due to arterioportal shunting. Arteriovenous shunting 111 causes high-output cardiac failure due to reduced systemic vascular resistance which in turn 112 leads to activation of the renin-angiotensin-aldosterone system, causing water and salt retention. 113 Portal hypertension occurs when the portal flow or vascular resistance is increased. Arterioportal 114 shunt is an uncommon cause of presinusoidal portal hypertension and is believed to be the result 115 of increased blood flow in the portal system. Hepatomegaly, ascites, bleeding episodes, and 116 splenomegaly can all be symptoms of portal hypertension. These clinical manifestations result 117 from deviations from Starling's law, where the force maintaining fluid in the vascular space is 118 less powerful than the force removing fluid from the vascular space.9 119 120 Follow-up of liver vascular malformations has shown up to 5% mortality and 25% morbidity 121 over a median follow-up period of 44 months.10 With the advent of cross-sectional imaging 122 modalities, visceral vascular manifestations are frequently detected. A recent study using 123 multidetector Computed Tomography (CT) has demonstrated hepatic involvement of around 74 124 – 79%.11,12 125 126 Hepatic involvement in HHT ranges from tiny telangiectasis to large confluent vascular masses. 127 Telangiectases are the most common vascular lesions seen in the liver in HHT.13 One of our 128 cases saw an incidental finding of telangiectasia in the liver (Case 2). Maximum Intensity 129 Projection (MIP) imaging helps appreciate these inconspicuous lesions from the hepatic 130 parenchyma as in our case. These telangiectasias can progress to form more complex vascular 131 malformations. Hence the patient has to be monitored for long-term follow-up. 132 133 Hepatic arteries are dilated and tortuous in HHT. Doppler study helps differentiate between the 134 dilated biliary radicles and tortuous hepatic arteries in HHT. In our case (Case 1), the hepatic 135 arterial velocity was similar to that of the mean velocity 153+/-65.2cm/s illustrated by Nagamuna 136 et al. in their study.14 137 138 Viyannan et al., in their case report, demonstrated that their patient had hepatic arterio-portal 139 shunting which was also seen in our case (Case 2).15 Proper phased protocol (arterial, portal, and 140 venous phase) helps in identifying inconspicuous shunting.13 141 142 In addition to dilated and tortuous hepatic arteries, a saccular aneurysm of the left hepatic artery 143 was found in our first case. However, very few cases of hepatic artery aneurysms have been 144 reported in the literature.16,17 There is still a paucity of qualitative research on the role of 145 intervention in the management of aneurysms in HHT. 146 147 Complications of Vascular Malformations (VMs) include recurrent endothelial damage and 148 micro-vascular thrombosis may eventually cause improper hepatocyte proliferation and fibrosis. 149 Cirrhosis development may ultimately result from chronic micro-vascular ischemia.18 150 Hepatic arterial insufficiency results in numerous types of ischemic biliary damage (ischemic 151 cholangiopathies). Several clinicopathological categories, including bile duct necrosis, bile leak 152 and biloma, biliary strictures, and biliary casts, make up ischemic cholangiopathies.19 153 154 Management of symptomatic hepatic VMs is mostly conservative. Patients manifesting with high 155 output cardiac failure are treated with salt restriction, diuretics, beta-blockers, ACE inhibitors, 156 digoxin, antiarrhythmic agents, cardioversion and radiofrequency ablation. Patients presenting 157 with complications of portal hypertension are treated with vasopressors, variceal ligation (for 158 variceal bleeding), diuretics (for ascites), lactulose and rifaximin (for encephalopathy). This is 159 accompanied by iron administration for anaemia along with definitive treatment for bleeding 160 sources. With this therapy, around 63% of patients show complete and another 21% show partial 161 response.10 162 163 In patients not responding to initial medical management, invasive options can be considered 164 including peripheral, staged trans arterial embolization of liver VMs.20 165 166 Liver transplantation is the only definitive curative option, indicated for intractable high-output 167 heart failure, complicated portal hypertension and ischemic biliary necrosis.21,22 Bevacizumab 168 was shown to reduce cardiac index in patients with severe liver VMs with high output cardiac 169 failure.23 Asymptomatic liver VMs at high risk of poor outcomes (grade 4) can be targeted for 170 prophylactic therapy.1 Sufficient data on the natural history and management of liver VMs are 171 lacking and there are no clear recommendations to prefer one treatment option over another. 172 173 Gastrointestinal telangiectases are rare manifestations of HHT. It generally affects the caecum or 174 colon and rarely the small intestine.24 An extensive literature search in Pubmed, Embase and 175 Cochrane, CT angiographic manifestations of gastrointestinal telangiectases is less reported. 176 Only one case of jejunal telangiectasis is reported.24 This article thus describes the CT 177 angiographic manifestations of ileal telangiectasis. 178 179 Conclusion 180 A cluster of findings led to high-end radiological suspicion, which unveiled the diagnosis of 181 HHT in one of our cases. Screening for hepatic VMs is recommended in asymptomatic 182 individuals suspected to have HHT as this leads to confirmation of diagnosis and better 183 management of these patients with Doppler ultrasound being proposed as a first-line 184 investigation. Ileal telangiectases should be considered in patients of HHT with gastrointestinal 185 bleeding. 186 187 Authors’ Contribution 188 AA and JHP drafted the manuscript. BS and MKP supervised the work. TT critically reviewed 189 and edited the manuscript. All authors approved the final version of the manuscript. 190 191 References 192 1. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-193 Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J. 2003 194 Jan;79(927):18-24. Doi: 10.1136/pmj.79.927.18. PMID: 12566546; PMCID: PMC1742589. 195 2. Piantanida M, Buscarini E, Dellavecchia C, Minelli A, Rossi A, Buscarini L, et al. Hereditary 196 haemorrhagic telangiectasia with extensive liver involvement is not caused by either HHT1 197 or HHT2. J Med Genet. 1996 Jun 1;33(6):441-3. 198 3. McDonald JE, Miller FJ, Hallam SE, Nelson L, Marchuk DA, Ward KJ. Clinical 199 manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J 200 Med Genet. 2000 Aug 14;93(4):320-7. 201 4. Canzonieri C, Centenara L, Ornati F, Pagella F, Matti E, Alvisi C, et al. 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PMID: 32066112; PMCID: PMC7025968. 268 269 270 https://www.google.com/search?newwindow=1&sxsrf=APq-WBv-6nYpU4JVc_SFEMJB-9NC6scefQ:1649917607557&q=Chavan+A,+Luthe+L,+Gabel+M,+Barg-Hock+H,+Seifert+H,+Raab+R,+et+al.+Complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+Eur+Radiol+2013;23:951%E2%80%93957.&spell=1&sa=X&ved=2ahUKEwius6CH9pL3AhVzR2wGHSW4B94QBSgAegQIARAz https://www.google.com/search?newwindow=1&sxsrf=APq-WBv-6nYpU4JVc_SFEMJB-9NC6scefQ:1649917607557&q=Chavan+A,+Luthe+L,+Gabel+M,+Barg-Hock+H,+Seifert+H,+Raab+R,+et+al.+Complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+Eur+Radiol+2013;23:951%E2%80%93957.&spell=1&sa=X&ved=2ahUKEwius6CH9pL3AhVzR2wGHSW4B94QBSgAegQIARAz https://www.google.com/search?newwindow=1&sxsrf=APq-WBv-6nYpU4JVc_SFEMJB-9NC6scefQ:1649917607557&q=Chavan+A,+Luthe+L,+Gabel+M,+Barg-Hock+H,+Seifert+H,+Raab+R,+et+al.+Complications+and+clinical+outcome+of+hepatic+artery+embolization+in+patients+with+hereditary+haemorrhagic+telangiectasia.+Eur+Radiol+2013;23:951%E2%80%93957.&spell=1&sa=X&ved=2ahUKEwius6CH9pL3AhVzR2wGHSW4B94QBSgAegQIARAz 271 Figure 1: Case 1 - (a and b) showing telangiectatic foci in pinna and hand (black arrows) (c) 272 Gray scale ultrasound image of the left lobe of the liver showing tortuous and dilated left hepatic 273 artery (white arrow) with corkscrew appearance; (d) Duplex Doppler image of left hepatic artery 274 shows normal waveform with markedly elevated peak systolic velocity (152 cm/s); (c and d) 275 276 277 Figure 2: Case 1 - CECT Arterial phase axial images (a, b) showing dilated and tortuous left 278 (LHA) and middle (MHA) hepatic arteries with evidence of arterio-portal shunting. LHA was 279 directly arising from the celiac trunk. MHA was seen as a direct continuation of the common 280 hepatic artery arising from the celiac trunk. A pseudoaneurysm (PA) is noted in the left lobe of 281 the liver arising from a branch of LHA. Liver contour is normal. Arterial phase coronal image (c) 282 showing dilated and tortuous right hepatic artery (RHA) arising from the superior mesenteric 283 artery (replaced RHA). 284 285 286 Figure 3: Case 2 - CECT Arterial phase axial image (a) showing mural enhancement in the 287 ileum (white arrow). Arterial phase axial images (b) showing multiple arterially enhancing 288 telangiectatic foci (black arrows) in both lobes of the liver. The hepatic artery is seen of normal 289 calibre with no arterio-portal shunting (c) enteroscopic image showing multiple punctate 290 telangiectases in ileum (black arrows). 291 a b c