961287 research-article20202020 TAG0010.1177/1756284820961287Therapeutic Advances in GastroenterologyJ Vidal-González, S Quiroga Therapeutic Advances in Gastroenterology Review Spontaneous portosystemic shunts in liver Ther Adv Gastroenterol 2020, Vol. 13: 1–19 cirrhosis: new approaches to an old problem DOI: 10.1177/ https://doi.org/10.1177/1756284820961287 https://doi.org/10.1177/1756284820961287 1756284820961287 © The Author(s), 2020. Article reuse guidelines: Judit Vidal-González, Sergi Quiroga, Macarena Simón-Talero and Joan Genescà sagepub.com/journals- permissions Abstract: Portal hypertension is the main consequence of liver cirrhosis, leading to severe complications such as variceal hemorrhage, ascites or hepatic encephalopathy. As an attempt to decompress the portal venous system, portal flow is derived into the systemic venous system through spontaneous portosystemic shunts (SPSSs), bypassing the liver. In this review, we aim to provide an overview of the published reports in relation to the prevalence and physiopathology behind the appearance of SPSS in liver cirrhosis, as well as the complications Correspondence to: derived from its formation and its management. The role of SPSS embolization is specifically Macarena Simón-Talero discussed, as SPSSs have been assessed as a therapeutic target, mainly for patients with Liver Unit, Department of Internal Medicine, recurrent/persistent hepatic encephalopathy and preserved liver function. Furthermore, Hospital Universitari Vall d’Hebron, Vall d’Hebron different aspects of the role of SPSS in liver transplantation, as well as in candidates Institut de Recerca (VHIR), for transjugular intrahepatic portosystemic shunt are reviewed. In these settings, SPSS Vall d’Hebron Barcelona Hospital Campus, occlusion has been proposed to minimize possible deleterious effects, but results are so far Universitat Autònoma de Barcelona, Pg. Vall inconclusive. d’Hebron, 119-129, Barcelona, 08035, Spain Centro de Investigación Keywords: collaterals, embolization, hepatic encephalopathy, liver transplant, portal Biomédica en Red de hypertension, review, TIPS Enfermedades Hepáticas y Digestivas, CIBERehd, Instituto de Salud Carlos Received: 9 June 2020; revised manuscript accepted: 2 September 2020. III, Madrid, Spain msimon@vhebron.net Judit Vidal-González Liver Unit, Department of Internal Medicine, Hospital Universitari Vall Introduction The close relation between SPSSs and HE is also d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Spontaneous portosystemic shunts (SPSSs) are reflected in the definition of HE: “Hepatic enceph- Vall d’Hebron Barcelona communications among the venous portal system alopathy is a brain dysfunction caused by liver Hospital Campus, Universitat Autònoma de and the venous systemic circulation that bypass insufficiency and/or portosystemic shunt”.10,11 Barcelona, Barcelona, the liver.1 Their presence has been related to por- Either persistent or recurrent HE has been linked Spain tal hypertension (PH).2 However, many ques- to the presence of shunts in many studies. Sergi Quiroga Radiology Department, tions regarding their prevalence, pathophysiology Moreover, the acquired experience with surgical Hospital Universitari Vall and repercussion in liver disease have not been shunts during the last century and lately with d’Hebron, Vall d’Hebron Barcelona Hospital completely elucidated. transjugular intrahepatic portosystemic shunts Campus, Barcelona, Spain (TIPS) has allowed achieving important knowl- Joan Genescà Liver Unit, Department Hepatic encephalopathy (HE) has been strongly edge in HE pathophysiology that is also applica- of Internal Medicine, linked with SPSS.3–5 This severe complication ble to SPSSs.12 Hospital Universitari Vall d’Hebron, Vall d’Hebron implies hospitalizations, high morbidity and mor- Institut de Recerca (VHIR), tality and detriment in quality of life among In recent years, patients with cirrhosis have an Vall d’Hebron Barcelona Hospital Campus, patients and their relatives.6,7 The generation of easier and widespread access to noninvasive Universitat Autònoma de nitrogenous-containing products in the gut, rich imaging techniques, not only ultrasound, but also Barcelona, Barcelona, Spain in ammonia, and the decrease in the cleaning abdominal contrast-enhanced computerized Centro de Investigación function in liver cirrhosis are involved in its patho- tomography (CT) or magnetic resonance (MR) Biomédica en Red de physiology.8 With the presence of SPSSs, a direct imaging, which have facilitated the diagnosis of Enfermedades Hepáticas y Digestivas, CIBERehd, bypass effect is added, amplifying the pass of tox- SPSSs.13 At the same time, SPSSs have been con- Instituto de Salud Carlos ins and the accumulation of ammonia.9 sidered as a therapeutic target to reverse difficult III, Madrid, Spain journals.sagepub.com/home/tag 1 Therapeutic Advances in Gastroenterology 13 cases of HE.14 More recently, special situations, cirrhosis evaluated for LT.32 A more recent study, as liver transplant (LT) or a broader TIPS indica- conducted by the Baveno VI Cooperation Group, tion, have posed new challenges, in which the role consisted of an international multicenter collabo- of SPSSs will have to be defined. ration that evaluated 1729 patients with liver cir- rhosis.25 SPSSs were present in 60% of the sample The aim of this review is to provide a comprehen- and half of them (488 patients, 28% from the sive revision of the role of SPSSs in cirrhotic total) were classified as large SPSSs, with a pre- patients, focused on clinical aspects and current established cutoff of 8 mm. This value was chosen therapeutic management. considering the smallest symptomatic embolized shunt reported in the literature.34 In this broad cohort, more than one-third of patients with large SPSS prevalence in liver cirrhosis SPSSs had also small SPSSs, and 9% had more How the prevalence of SPSSs has been evaluated than one large SPSS.25 Other authors have also has changed over time. The initial postmortem identified more than one SPSS in 22–25% of studies15,16 were followed by diagnostic techniques, their sample.27,31 Rodriguez et al. provided recent such as splenoportography, angiography or percu- data from a cohort of 326 patients with cirrhosis taneous transhepatic portography.17 These proce- and candidates for LT in which a high rate of dures were replaced by current noninvasive SPSS was found (almost 80%), with a slight pre- imaging techniques, such as Doppler ultrasound, dominance of small SPSSs (46% from the total) contrast-enhanced CT or MR imaging.13 over large SPSSs (35%).33 However, assessing the true prevalence of SPSSs Many studies have evaluated the type of shunt is still a matter of discussion; most studies are ret- detected,25,27–29,32,35,43 and most of them have rospective and include small samples of patients, focused on the identification of a specific type of not always comparable in liver function or even SPSS (Table 1).30,31,36–42,44,46 Paraumbilical vein basal liver disease. The different diagnostic meth- shunt was the most frequently reported SPSS, ods used over time or technical improvements in found in up to 43% of patients30,31,35–38,47 and a specific method make comparisons among stud- even 59% when combined with other SPSSs.39 ies difficult.18 Doppler ultrasound provides useful Despite the high prevalence, its classical information about the presence and direction of advanced form as caput medusa is rarely seen.48 portal flow or flow within a shunt.19 Nevertheless, The left renal vein is frequently involved in por- it is operator-dependent and may under-diagnose tosystemic collateral drainage: splenorenal (10– deeper collaterals.20 By contrast, CT and MR 23%) and gastrorenal shunts (5–11%) were also provide cross-sectional imaging, which allows frequently described.28,32,40,42–44 By contrast, observing the whole portal system.13 Currently, splenorenal shunt was the most frequent large contrast-enhanced abdominal CT seems the most SPSS found in the Baveno VI Cooperation appropriate imaging technique for searching Group cohort.25 Mesenteric collaterals from shunts, considering availability, costs, informa- superior and inferior mesenteric veins are also tion provided and the possibility of performing a present in many series in a lower percent- three-dimensional reconstruction.21 MR imaging age.25,32,35,43 Intrahepatic SPSSs are rare and is as accurate as CT22 but is more expensive and very infrequently reported49 (Figures 1 and 2). might be less available.23 According to the anatomical drainage, different Even the definition of a SPSS is not always com- theoretical classifications have been proposed1,43,50 parable, as some studies considered gastroesoph- depending on its situation (left-sided shunt, ageal varices (GEVs) as a type of SPSS24 and including gastrorenal and splenorenal shunt, and others exclude varices from the classification.25,26 right- or central-sided shunt, which includes With these limitations, the largest series available paraumbilical shunts),17,51 or according to the performed by ultrasound estimate the global per- manner the shunt reaches its drainage in the renal centage of SPSSs between 34% and 42%.27–31 vein (named direct splenorenal shunts in the left There are fewer studies carried out with enhanced subfrenic compartment or indirect splenorenal CT or MR imaging with data about general prev- shunt, also called gastrorenal shunts).47 This alence (Table 1).25,32,33 Aucejo et al. identified information has special interest in the surgical 12% of SPSSs in a cohort of 127 patients with approach of LT. 2 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. Table 1. Prevalence and types of SPSSs. Reference Imaging Number of Prevalence of SPSS Type of SPSS number (percentage from test patients evaluated number (percentage) the total sample, unless specified) Cho et al.35 CT 60 NA - Coronary venous: 48 (80) - Paraumbilical: 26 (43) - Abdominal wall: 18 (30) - Perisplenic: 18 (30) - Mesenteric: 6 (10) - Splenorenal: 6 (10) - Gastrorenal: 4 (7) Sacerdoti et al.36 DUS 184 NA - Paraumbilical: 62 (33.7) Von Herbay et al.27 DUS 109 41 (38) - Splenorenal: 16 (15) - Paraumbilical: 8 (9) - Gastric: 2 (2) - Combinations (>1 SPSS): 9 (8) - Others: 5 (5) - Without SPSS: 68 (62) Dömland et al.37 DUS 70 NA - Paraumbilical: 16 (23) Chen et al.38 DUS 254 NA - Paraumbilical: 28 (11.1) Del Piccolo et al.39 DUS 95 NA - Paraumbilical: 56 (59) - Alone: 31 (33) - Combination: 25 (26) Berzigotti et al.30 DUS 126 42 (33.3) - Paraumbilical: 23 (18.2) - Splenorenal: 13 (10.3) - Left Gastric Vein: 11 (8.7) - Others: 5 (3.9) Aucejo et al.32 CT 127 16 (12.6) - Splenorenal: 12 (9.4) - Coronary: 2 (1.6) - IMV cava: 1 (0.8) - Others: 1 (0.8) Zardi et al.28 DUS 326 130 (39.9) - Splenorenal: 45 (13.8) - Left gastric vein: 36 (11) - Combination: 25 (7.7) - Paraumbilical: 24 (7.4) - Without SPSS: 196 (60.1) Tarantino et al.40 DUS 81 NA - Splenorenal: 15 (18.5) Berzigotti et al.31 DUS 86 36 (42) - Paraumbilical: 17 (19.8) - Left gastric vein: 15 (17.4) - Splenorenal: 6 (10.0) - Short gastric vein: 5 (5.8) Kondo et al.41 DUS 181 NA - Paraumbilical: 47 (26) Maruyama et al.42 DUS 162 NA - Splenorenal: 30 (18.5) - Short gastric vein: 17 (10.5) Achiwa et al.43 CT 451 NA - Splenorenal: 50 (11.1) - Gastrorenal: 23 (5.8) - Paraumbilical: 8 (1.8) - Mesocaval: 3 (0.7) - Others: 2 (0.4) (Continued) journals.sagepub.com/home/tag 3 Therapeutic Advances in Gastroenterology 13 Table 1. (Continued) Reference Imaging Number of Prevalence of SPSS Type of SPSS number (percentage from test patients evaluated number (percentage) the total sample, unless specified) Simón-Talero et al.25 CT (1630) 1729 1036 (60) Large SPSS: MRI (99) - Large SPSS: 488 (28%) - Splenorenal: 224 (46)a - Small SPSS: 548 (32%) - Paraumbilical: 132 (27)a - Without SPSS: 693 (40%) - Gastrorenal: 44 (9)a - Mesocaval: 25 (5)a - IMV cava: 20 (4)a - Others: 35 (7)a Small SPSS: - Paraumbilical: 296 (54)b - Splenorenal: 99 (18)b - Gastrorenal: 83 (15)b - Mesocaval: 44 (8)b - IMV cava: 3 (0.5)b - Others: 20 (3.5)b Lipinski et al.29 DUS 982 338 (34) - Paraumbilical: 232 (68.6)c - Splenorenal: 55 (16)c - Mesenteric: 24 (7)c - Combination: 27 (8)c Saks et al.44 CT 741 NA - Splenorenal: 173 (23) Gómez-Gavara CT 429 75 (17.5)d - Splenorenal: 40 (60.6)c et al.45 MRI - Left gastric: 16 (24.2)c - Mesenterico-iliac: 10 (15.1)c Rodríguez et al.33 CT/MRI 326 263 (80.7%) - Large SPSS: 113 (35%) - Small SPSS: 150 (46%) - Without SPSS: 63 (19%) CT, computed tomography; DUS, Doppler ultrasound; IMV, inferior mesenteric vein; MRI, magnetic resonance imaging; NA, data not available and not possible to calculate with the data provided; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt. aPercentage from the total of Large SPSS. bPercentage from the total of Small SPSS. cPercentage from the total of SPSS. d9 patients with SPSS were excluded due to extent PVT and type of SPSS is not mentioned. A specific relationship between etiology and the appear after reopening closed embryonic venous type of shunt has been suggested. In some series, it channels that communicate venous portal flow was observed than paraumbilical veins were more with the systemic circulation, bypassing the liver. frequent among alcohol-related cirrhosis than in Moreover, there are evidences supporting that viral hepatitis.25,29,38 These results, however, are SPSSs are not only developed from pre-existing not consistent in all studies and should be con- vascular channels, but also as new vessels formed firmed. Hepatocellular carcinoma has also been in a process of neoangiogenesis.52,53 related to SPSSs with inconclusive and contradic- tory results.29,33,40 An explanatory model for the compensatory mechanism and development of SPSSs has been proposed, equating it to an electrical circuit.54 The Pathophysiology authors rely on Ohm’s law to propose two varia- The development of collaterals is directly linked bles involved. The increase in portal venous pres- to the presence of PH; SPSSs are formed as a sure (PVP) and the decrease in shunt resistance compensatory mechanism, in an attempt to (SR), defining the shunt flow as PVP/SR. When decompress the portal venous system. Collaterals PVP has a significant increase as a consequence of 4 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. liver cirrhosis, shunt flow rises. In the same way, if SR decreases, shunt flow would increment, as it occurs in aneurysmal dilations of the vascular channels. Secondarily to these events, PVP and portal blood flow would be reduced, due to the circuit bypass created by the shunts. This model has therapeutic implications; the increase of PVP after SPSS occlusion should be taken into consid- eration when an embolization is been planned, as PVP could increase enough to open new shunts.14 The development of SPSS seems also to have implications on liver function. Kumamoto et al. proposed the term “portosystemic shunt syn- drome” referring to a significant reduction of hepatic reserve (reflected by progression of Child– Pugh score) over 5 years, as compared with patients with cirrhosis and PH without gastrorenal shunts.55 Saad et al. based on this concept, described a com- plete syndrome with clinical manifestations and imaging findings56 that developed in three phases: (1) early stage, characterized by few episodes of HE and relatively well-preserved liver function; (2) late stage, in which overt HE is more frequent and liver function starts to deteriorate; radiological signs include incipient liver atrophy, disappear- ance of portal branches and the possibility of portal thrombosis; in the main portal vein, the hepato- petal flow becomes sluggish; and (3) end stage, in which HE is markedly disabling, the patient has advanced liver failure and portal thrombosis or liver atrophy are easier to find; portal flow can reverse and become hepatofugal. Thus, despite the fact that a SPSS is initially a compensatory mecha- nism, as PH progresses, the shunt increases in size, Figure 1. Contrast-enhanced CTs of different SPSS. worsening the bypass effect and contributing to the (a) Gastrorenal shunt (thin arrows). Thick arrows: varices of coronary vein. Coronal image and two volume rendering images. (b) Paraumbilical shunt that drain deterioration of liver function.57 through collaterals (thick arrows) to the right common femoral vein. Thin arrows: paraesophageal varices. Four axial images and two volume rendering images. (c) Paraumbilical shunts deserve a special mention. Splenorenal shunt (thick arrows) that communicates with left renal vein through left Their development occurs due to the expansion of gonadal vein (arrowhead). Secondary peri-ureteral collaterals (thin arrows). Coronal image, maximum intensity projection coronal image and volume rendering image. (d) paraumbilical veins, normally collapsed, located at Mesocaval shunt (thick arrows), from SMV to IVC (thin arrows) through right gonadal the falciform ligament. When they are the only SPSS vein. Coronal image and two volume rendering images. present, significant blood volume circulates through CT: computed tomography; IVC, inferior vena cava; SMV, superior mesenteric vein; the portal vein with hepatopetal direction.37,57 SPSS, spontaneous portosystemic shunt. However, these characteristics do not imply an effec- tive portal perfusion and do not confer a protective role: as other SPSSs, paraumbilical veins are ­specially studies, with different conclusions (Table 2). On identified as liver function deteriorates.36–38 one hand, the presence of SPSS has been linked to an increase of PH-related complications, such as ascites or GEVs.3,25,30,31,58 By contrast, a pro- Clinical studies and complications related tective effect has also been proposed. A decrease to SPSS in the rate of ascites, varices and gastrointestinal The relation between PH complications and bleeding (GIB) in patients with large SPSSs has SPSS has been considered in many clinical been described, especially in those cases with journals.sagepub.com/home/tag 5 Therapeutic Advances in Gastroenterology 13 Figure 2. Embolization of SPSS from IMV to ICV. (a) Dilated IMV (arrows) and large shunt (arrowhead), that drains to ICV. Volume rendering image. (b) Contrast-enhanced shunt during the angiographic procedure, showing the drainage of the collateral from IMV to IVC. Angiography image (digital subtraction ). (c) After the embolization with Amplatzer (arrowhead), distal diameter of IMV was reduced (thick arrows). New collaterals through left colic vein (thin arrows) to IVC were developed. Volume rendering image. CT: computed tomography; IVC, inferior vena cava; IMV, inferior mesenteric vein; SPSS, spontaneous portosystemic shunt. HE.59,60 Onishi et al. showed that patients with SPSSs more often had HE, variceal bleeding, splenorenal or gastrorenal shunts and HE pre- ascites, spontaneous bacterial peritonitis and hepa- sented fewer esophageal varices (EVs) and a torenal syndrome.25 These differences were espe- reduced incidence of episodes of GIB.59 Takashi cially significant in patients with preserved liver et al. also found a protective effect, with a low per- function, that is, patients with a Model for End- centage of EVs in patients with shunts and HE.60 stage Liver Disease (MELD) score of 6–9 or In a case–control study performed by Riggio Child–Pugh A. et al., patients with SPSSs had fewer EVs and ascites, supporting a protective and compensa- Some reports have highlighted an association tory mechanism.5 Tarantino et al. showed that between a specific type of collateral and different patients without SPSSs had a higher rate of large complications. For varices, different drainage has EVs.40 Finally, Saks et al. identified a higher per- been proposed according to GEVs (or EVs) or centage of EVs, but a lower probability of ascites.44 gastric varices (GVs) alone: EVs/GEVs are com- monly supplied from the coronary/left gastric These results, however, contrast with other vein; GVs alone are frequently supplied from the ­studies,3,25,27–31,36,41,42,58 in which patients with short or posterior gastric veins, and are closely SPSSs presented, in addition to HE, signs of clini- linked to gastrorenal shunts,62 also suggesting a cally significant portal hypertension as varices or PH-related mechanism. Paraumbilical veins have ascites. In the cohort provided by Aseni et al. the been related to a lower risk of GIB, considering whole group with SPSSs had GIVs, with a rate of its hemodynamical effect (potentially less spleno- bleeding of 60%.58 Berzigotti et al. showed that the megaly, smaller portal diameter, hepatopetal por- appearance of SPSSs had a correlation with the tal vein flow with high velocity);28 however, these development or worsening of GEVs.30 In another results have not been sustained by other study performed by the same group, 89% of groups.25,58 Lipinski et al. found a specific rela- patients with cirrhosis and SPSSs had an hepatic tionship between paraumbilical shunt and venous pressure gradient (HVPG) higher than ascites,29 not described in other cohorts. 16 mmHg, which was linked to an increased risk of complications and death.31 Park et al. also found These contradictory findings are probably high HVPG in patients with GEVs and SPSSs (gas- explained due to the cross-sectional nature of trorenal and/or splenorenal shunts), without detect- most studies, which has hindered the interpreta- ing differences with the group without SPSSs tion of the results. Liver cirrhosis is a dynamic (18.3 ± 5.8 versus 17.0 ± 8.1 mmHg, respec- disease with different stages and compensatory tively).61 In the large clinical study driven by the mechanisms, difficult to understand in a static Baveno VI Cooperation Group, patients with moment. As explained, SPSSs participate as part 6 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. Table 2. Relation between SPSS and decompensating events (GEV, ascites and HE), and liver function. Studies in which percentage of GEV, GIB, presence of ascites, HE or liver function are mentioned, are detailed on the table. REF Gastroesophageal varices Gastrointestinal Ascites Hepatic Encephalopathy Liver Function Bleeding Lam3 SPSS: 95% No-SPSS: NA No differences No differences Dig Dis Sci 1981 Takashi4 Lower % in SPSS + HE vs SPSS Not available (case- control No differences J Hepatol 1985 without HE (14% vs 92%)** study) Onishi59 EV: Lower % in SPSS + HE vs No differences No differences SPSS: 46% SPSS + HE: Worse Am J Gastroenterol SPSS without HE or no-SPSS No-SPSS: Not valuable albumin and bilirubin 1986 (45%; 87%; 97%)*** (pre-defined inclusion than no-SPSS* GV: Lower % in SPSS without HE criteria) (27%; 7%, 30%)$ Sacerdoti36 No differences Higher % in SPSS SPSS: Worse Child-Pugh Hepatology 1995 vs no-SPSS (8.6 ±2.2 vs 7.4±1.7)*** (61.3% vs 37.7%)* Von Herbay27 Higher % in SPSS vs no-SPSS Higher % in SPSS SPSS: Lower % in Child- J Clin Ultrasound 2000 (93% vs 66%)** vs Pugh A vs B/C no-SPSS (27%; 46%; 44%)* (61% vs 32%)** Dömland37 SPSS: Lower % in Child- Ultraschall Med 2000 Pugh A vs B* vs C** (6.3%;25.9%;33.3%) Chen39 SPSS: Lower % in Child- AJR 2002 Pugh A vs B*** vs C*** (2.4%;11.3%;22.6%) Del Piccolo39 Higher risk with low Metab Brain Dis 2002 effective portal flow: - altered neuropsychological test (60% vs 40%)*** - altered EEG (63% vs 37%)*** Riggio5 Lower % of large EV among Lower % of ascites Hepatology 2005 HE vs among HE vs no- no-HE HE (21% vs 78%)** (7% vs 42%)*** Berzigotti30 No differences at baseline. SPSS: Higher % of SPSS: Higher Digest Liver Dis 2008 Higher formation of VE in new ascites Child-Pugh vs no-SPSS SPSS over time (35.7% vs 14.3%)** (7.6±1.8 vs 6.0±1.3)*** (56.2% vs 22.2%)* Higher progression in new SPSS (52.9% vs 30.6%)* Zardi28 Higher % in SPSS vs no-SPSS SPSS: Lower % in Child- J Gastroenterol 2009 (64% vs 53%)* Pugh A vs Child B/C*** Tarantino40 Lower % of large EV in SPSS vs No differences No differences No differences BMC Gastroenterology no-SPSS 2009 (7% vs 45%)** Berzigotti31 Higher % in SPSS J Gastroenterol 2011 vs no-SPSS (52% vs 9%)** Kondo41 Higher % in SPSS No differences at No differences No differences J Clin Gastroenterol vs no-SPSS baseline 2014 (75% vs 46%)** Higher % in SPSS over time (33.3% vs 2.9%)* (Continued) journals.sagepub.com/home/tag 7 Therapeutic Advances in Gastroenterology 13 Table 2. (Continued) REF Gastroesophageal varices Gastrointestinal Ascites Hepatic Encephalopathy Liver Function Bleeding Maruyama42 EV: No differences No differences No differences No differences No differences Scand J Gastroenterol GV: Higher % in SGV vs SRS 2015 and no-SPSS (100%; 0%; 14.8%) Qi46 No differences No differences No differences SPSS: Worse Child-Pugh Med Sci Monit 2017 and MELD Simón-Talero25 GEV: Higher % in large and Higher GIB in large Higher % in large Higher % in Large- SPSS: Worse Child-Pugh Gastroenterology 2018 small SPSS and small SPSS vs and small SPSS vs SPSS > Small SPSS > no- and MELD (Large- vs no-SPSS no-SPSS no-SPSS SPSS (32%,19%;8%)*** SPSS > (EV:71%;71%;59%)*** (25%;26%,11%)*** (57%; 55%; 32%)*** Small SPSS > (GV: 10%; 7%;4%)* no-SPSS (13;11;9)*** Lipinski29 Higher % in SPSS No differences No differences Higher % in SPSS (25-30% SPSS: Worse Child- Scand J Gastroenterol (60-65% vs 50-55%)** vs 10-15%)*** Pugh*** and MELD 2018 vs no-SPSS (15; 13)*** Saks44 No differences Lower % in SPSS No differences No differences in MELD Hepatology vs no-SPSS (43% score Communications 2018 vs 59%) ** * <0.05; ** <0.01; *** <0.001; $: unknown-p value; EV: Esophageal varices; GV: Gastric varices; GEV: Gastroesophageal varices; HE: Hepatic encephalopathy; MELD: Model for End Stage Liver Disease; SGV: Short Gastric Veins; SPSS: Spontaneous portosystemic shunt; SRS: Splenorenal shunt. of the compensatory measures, initially reducing chronic HE, while only 14% of the group without PVP and decreasing the number of PH-related HE presented SPSSs.5 Similarly to TIPSs, a rela- complications. As the disease advances, SPSSs tion between SPSS size and HE has been may be insufficient, and not only fail to decrease observed.25,33,66 In the recent work by Praktiknjo PVP, but also contribute to reduce liver perfu- et al. large SPSSs, classified according to the total sion, worsening liver failure.57,63 shunt area, had higher risk of developing HE and higher ammonia levels.66 This hypothesis is reinforced by the fact that patients with SPSSs showed worse liver function In addition to size, the presence of hepatofugal in many studies (assessed both Child–Pugh class blood flow in SPSSs is also an important compo- and MELD score).25,27–29,36–38,42 In the largest nent for developing HE.59 Both size and hepatof- published cohort previously mentioned, patients ugal flow support the bypass mechanism in which with large SPSSs had higher Child–Pugh and blood flow circulating through SPSSs, carrying MELD score than those with small collaterals, neurotoxins from intestine, bypasses the liver.67 and both had worse liver function than patients Some studies have suggested that paraumbilical without shunts.25 shunts, responsible for hepatopetal flow in the portal vein, do not influence HE.4,28 However, larger series have provided evidence against this Hepatic encephalopathy hypothesis, with the same rate of HE complica- The relation between HE and the presence of tions than other SPSSs,25,68 supporting the con- shunts is well known. Moreover, in recent dec- cept of “ineffective portal flow”.39 ades, surgical shunts and, more recently, TIPS placement have allowed acquiring a wide experi- As a result of these mechanisms, patients with cir- ence in HE.64,65 Previous reports have observed rhosis and SPSSs can develop HE with a relatively that 46–71% of patients with recurrent and/or preserved liver function and have less identifiable persistent HE showed large SPSSs at radiological precipitating events.3 In this setting, the SPSS examination.5,59 In the case–control study per- would act as a facilitating factor. Nevertheless, the formed by Riggio et al. with 28 patients, large presence of SPSSs alone is not enough for explain- SPSSs were identified in 71% of patients with ing the development of HE; in patients with 8 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. noncirrhotic portal hypertension who develop Embolization portosystemic collaterals, in whom liver function Interventional radiology embolization is a useful is preserved, HE is rarely seen.69 HE is driven by technique for the management of PH-related the accumulation of those neurotoxins due to liver complications of SPSSs, especially gastrorenal disease and aggravated by SPSSs.67,70 shunts with associated GV.1 Balloon-occluded retrograde transvenous obliteration (B-RTO) is Therefore, large SPSSs should be investigated in an effective method to control GV bleeding, fre- patients with HE, especially in recurrent or per- quently used in Asia.13 It has also showed effec- sistent episodes despite relatively well-preserved tiveness as treatment of HE associated with liver function.10,11 Also, a high rate of covert HE GVs.83 However, the secondary increase in PVP has recently been reported among these patients, can worsen other PH-related complications, as associated with a significant risk of developing EVs or ascites. Moreover, the sclerosing material overt HE.71 For the diagnosis of SPSS, a high could also produce secondary effects, as pulmo- index of suspicion is needed, as abdominal CT is nary edema or portal vein thrombosis.51 Other not routinely performed in cirrhotic patients and techniques as coil-assisted retrograde transvenous abdominal ultrasound could not identify deep obliteration (CARTO) or vascular plug-assisted SPSSs.72 transvenous obliteration (PARTO) have been developed, providing the same results with less There is a special form of HE with cerebellar and secondary effects.84,85 extrapyramidal symptoms called hepatocerebral syndrome or cirrhosis-related Parkinsonism, in Regarding HE, the presence of shunts not only which large SPSSs are frequently identified.73 In justifies the refractivity to treatment but also pro- this condition, T1 hyperintensity in basal ganglia vides a therapeutic target.86 However, the possi- due to manganese deposition is commonly bility of increasing PH after embolization, as well described in cerebral MR imaging, suggesting a as causing procedure-related complications, mechanism of toxicity.74 This clinical presenta- should be carefully considered. tion does not respond to classical ammonia-­ lowering treatments,75 and neither has the effect In the last 40 years many publications have pro- of levodopa been well established.76 Nevertheless, vided experience in SPSS embolization in HE. shunt occlusion (discussed in next section) and Initially, the level of evidence was limited to case LT have been suggested as therapeutic options,77 reports and short series, even with contradictory provided that other etiologies are excluded. results. However, in the past decade, larger series Hepatic myelopathy is a very infrequent type of have been reported, and have allowed obtaining HE, characterized by progressive spastic parapa- homogeneous conclusions.68,87–91 It has been resis and hyper-reflexia.10,11 that has been related proved that embolizing shunts to treat refractory to long-standing shunts in most of the cases, up to HE is both efficient and safe, in well-selected 85%.78 Its management includes, with limited patients (Table 3). Three months after emboliza- experience, LT, which can achieve an improve- tion, around 60% of patients remain free of neu- ment in symptoms especially in earlier stages.79,80 rological symptoms68 and a high percentage remain free of HE at 1–2 years (49–55%).68,87,88 The importance of identifying SPSSs rests in the Late recurrences are probably related to develop- possibility of improving measures against HE.10,11 ment of new collaterals or recanalization of previ- These patients may benefit from intensive man- ously closed ones.14 agement and closer follow-up, optimizing treat- ment (with nonabsorbable disaccharides and also Severe procedure-related complications, includ- considering the addition of antibiotics as rifaximin) ing thrombosis, or aggravation of PH-related fea- and providing recommendations about avoiding tures such as GIB or ascites, have not been precipitating events (as constipation, use of seda- observed in a significant proportion (Table 3). In tive drugs, diuretic treatment overuse, and early the different series published, patients were care- identification and treatment of infections).70,81 If fully selected before the procedure. Patients with despite these measures, recurrent or persistent HE severe/refractory ascites or large GEVs were not is maintained, second-line more-invasive manage- considered as candidates to embolization. MELD ment should be considered.82 These approaches score pre-embolization has been identified as a will be developed in the next section. good predictor of outcomes, with a range of journals.sagepub.com/home/tag 9 Therapeutic Advances in Gastroenterology 13 Table 3. Efficacy and safety in SPSS embolization. Main results from recent studies that evaluate efficacy and safety of embolization. Reference n SPSS Embolization (access, material Efficacy/Safety and technique) Laleman 37 Splenorenal: 20 Percutaneous (paraumbilical); % free of HE: et al.68 Paraumbilical: 9 transhepatic (the others) - Short-term (100 days): 59.4%* Mesocaval: 7 Material: coils (59%), Amplatzer - Long-term (2 years): 48.6%* Mesorenal: 1 plugs (35%), matrix or a - Procedure-related complications: combination 7 mild/1 capsular bleeding - Long-term: De novo EV: 2 (1 small, 1 large) GEV: no significant increase EV bleeding: 1 nonfatal at 55 months Ascites: no significant differences PVT: 4 (11%; 1 in PV, 3 in one branch) Lynn et al.87 20 Splenorenal: 12 Transhepatic (25%), also right % HE with sustained improvement femoral, internal jugular, - Short-term (1–4 months): 100%** paraumbilical, right axillary. - Long-term (6–12 months): 92%** Material: coils (75%), Amplatzer - Procedure-related complications: 10% plugs (20%) or combination 1 mild/1 bacterial cholangitis - Long-term (12 months): De novo EV: 1 (small) Ascites (new or worsening): 6 (4 paracentesis) An et al.88 17 Splenorenal: 14 Percutaneous (paraumbilical); Recurrence of OHE for 2 years: Paraumbilical: 3 femoral (splenorenal) 39.9% (embolized) versus 79.9% (control)* Material: Amplatzer plugs, coils - No serious procedure-related complications combined with gelatin sponges - Long-term: MELD ⩽ 15 and no HCC Ascites: mild 3 (18%) EV (small-sized new or worsened): 3 (18%) No GIB No PVT Naeshiro 14 Splenorenal: 3 Percutaneous HE disappearance in 1–2 weeks: 93% et al.89 Gastrorenal: 4 Material: EOI, coils and NBCA - No serious procedure-related complications Mesocaval: 5 (B-RTO or CARTO) - Long-term: Portocaval: 2 EV: worsening at 3 months (21%) EV: worsening at 24 months (29%) GIB: 14% Inoue et al.90 19 Splenorenal: 19 EOI, coil and NBCA HE improvement: 100%* (B-RTO) - No serious procedure-related complications - Long term: ascites: 21% Philips 21 Splenorenal: 17 Transjugular (71%), transhepatic HE improvement: et al.91 Mesocaval: 7 (19%), transfemoral (4.8%) - Short-term follow up: 71%* plus others CARTO, PARTO, B-RTO or a - Long-term: 23% combination Serious procedure-related complications: 1 hemoperitoneum with multiple organ failure - Long-term: EV: No significant increase GIB: 1 nonfatal, controlled with band ligation (122 days post-occlusion). Ascites: no significant increase B-RTO, balloon-occluded retrograde transvenous obliteration; CARTO, coil-assisted retrograde transvenous obliteration; EOI, ethanolamine oleate with iopaminol; EV, esophageal varices; GEV, gastroesophageal varices; GIB, gastrointestinal bleeding; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma; NBCA, N-butyl cyanoacrylate; MELD, Model for End-stage Liver Disease; OHE, Overt hepatic encephalopathy; PARTO, vascular plug-assisted transvenous obliteration; PVT, portal vein thrombosis; SPSS, spontaneous portosystemic shunt. *p < 0.05. **Per-protocol analysis. 10 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. Figure 3. Algorithm including persistent or recurrent HE suggested management, considering SPSS embolization or liver transplant. HE, hepatic encephalopathy; SPSS, spontaneous portosystemic shunt. cutoffs from 11 to 15; patients with higher MELD lack of benefit and more mortality after shunt will probably not benefit from embolization68,87,88 occlusion.14 The limited evidence available estab- and show worse outcomes and more complica- lishes a Child–Pugh score >11 as a cutoff. In case tions. In a recent work, low liver stiffness values of hepatic myelopathy, the usefulness of this tech- measured by transient elastography, were linked nique has not been determined, due to its with better outcomes; the cutoff used was extremely low frequency. Currently, the experi- 21.6 kPa, which correlates with clinically signifi- ence is limited to isolated case reports, in which cant portal hypertension.92 this alternative approach is also recommended to patients with preserved liver function.93 Therefore, patients with recurrent or persistent HE secondary to SPSSs with deteriorated liver function and PH-related complications should be consid- Portopulmonary hypertension ered as candidates for LT. By contrast, when liver SPSS are associated to other less frequent com- function is preserved, shunt embolization would plications, such as portopulmonary hypertension be a recommended and less-invasive approach.82 (POPH). POPH is defined by hemodynamic cri- (Figure 3) Shunt embolization would avoid con- teria assessed by right heart catheterization in the tinuous episodes of HE in patients with good liver presence of portal hypertension, with or without function that would remain for a long time on the cirrhosis. The association between SPSSs and waiting list.86 POPH is not completely understood. SPSS may probably increase the pulmonary flow but also With regard to cirrhosis-related Parkinsonism, facilitate the transit of substances, such as vasoac- the experience is very limited, but in the same tive factors, which are produced in the splanchnic direction; Parkinsonism and HE symptoms can circulation.94 These factors skip the liver and pro- improve significantly after shunt embolization in duce vasoconstriction in the pulmonary vascular carefully selected patients.91 As in the previously bed.95 It has been shown that the frequency of mentioned studies, deteriorated liver function is a shunts is similar between patients without and contraindication for this therapeutic option, with with POPH, including mild and moderate/severe journals.sagepub.com/home/tag 11 Therapeutic Advances in Gastroenterology 13 POPH. Nevertheless, large SPSSs are more fre- placement is preferably performed in selected quently seen among the latter. Moreover, the patients with enough hepatic reservation and if presence of large collaterals is significantly associ- possible, without previous episodes of HE, with ated with treatment failure.96 In many cases, the chronic HE being a relative contraindication.103 appearance of SPSSs precedes the diagnose of POPH, therefore identifying a subgroup of Saad and Darcy compared the experience of patients at risk of both developing POPH and TIPS placement and B-RTO in the management treatment failure, whom may benefit from a closer of GV bleeding by evaluating the hemodynamic follow-up, screening and prompt treatment. and liver function consequences of both tech- niques.104 As previously mentioned, GVs alone are frequently supplied from posterior or short Survival gastric veins through a gastrorenal SPSSs. The SPSSs have been suggested as an aggravating fac- authors suggest that the amount of portal blood tor for liver disease, worsening hepatic failure by flow diverted through the gastric shunt should be decreasing blood supply.55 This effect is well taken into account as a predictor of response. known in surgical and radiological shunts, and Following this argument, the possible conse- has been previously discussed as the “portosys- quences of TIPS placement in case of gastrorenal temic shunt syndrome”.97,98 In this sense, embo- shunt were analyzed around the so-called lization of SPSSs in selected patients could offer “throughput theory”, according to which a sig- extra benefit. Some studies indeed have pointed nificant gastrorenal shunt could act as a compet- out a protective role of the procedure, improving ing shunt. Also, the influence of the anatomical liver function and even reducing mortal- situation was proposed as the “proximity theory”, ity.55,88,90,99 Ishikawa et al. found that patients in which the location of the posterior or short gas- with low basal stiffness (up to 21.6 KPa) showed tric veins, closer to gastrorenal shunts than to an improvement of MELD sodium score and TIPSs, was introduced as another competing fac- higher survival after embolization.92 tor. In contrast, coronary/left gastric veins, which usually drained to EVs, have their origin in the In the study conducted by the Baveno VI right side of the portal circulation, closer to the Cooperation Group, a relevant relation between portal system; this anatomical differences could SPSSs and mortality was identified.25 SPSSs were explain the more effective role of TIPS in EVs.104 independently associated with mortality or LT, with significant differences in the group of patients Although recent data suggest that rifaximin has a with preserved liver function (MELD score of 6–9). protective effect, reducing the risk of HE after No relation between mortality and SPSS size or TIPS when administered 15 days before the proce- anatomical type was identified. Nevertheless, dure and maintained 6 months after,105 it can be Praktiknjo et al. recently used the sum of the cross- insufficient in some cases. Some studies suggest sectional areas of all SPSSs identified, finding that that pre-existing large SPSSs increase the risk of a large SPSS area (>83 mm2) was associated with post-TIPS HE, which diminishes when these worse survival.66 The main interpretation of these shunts are embolized.106–109 After TIPS placement, results is that the area allows to magnify the differ- nearly one-third of SPSSs remained unchanged, ences between patients, and that the sum of the although with a reduction in portal pressure. He area is a more reliable information about the et al. proposed prophylactic embolization of SPSS attempt to compensate PH, reflecting more clearly during TIPS, and showed that the risk of HE was the real hemodynamic situation and clinical course similar to those without shunts [hazard ratio (HR) of patients. for HE in 5 years of 1 (TIPS) versus 1.38 (1.08– 1.77) (TIPS + SPSS) versus 0.82 (0.49–1.37) (TIPS + embolization); p = 0.029].106 They also SPSS and outcomes after TIPS showed that these patients did not have a higher TIPS placement has become an established ther- risk of rebleeding, recurrence of ascites, TIPS dys- apy for PH-related complications, including function or death of any cause. Similar results were refractory ascites and acute or recurrent GEV obtained by Leng et al. in a recent study that evalu- bleeding.100–102 Its main limitation is the risk of ated the efficacy of TIPS combined with SPSS liver dysfunction and the development of HE after embolization in variceal bleeding, comparing the the procedure.64,65,98 That is the reason that TIPS results and risks with patients without SPSSs.107 In 12 journals.sagepub.com/home/tag J Vidal-González, S Quiroga et al. this study, a control group submitted to TIPS with Nevertheless, an association between SPSSs and nonembolized SPSSs was not included. By con- more complications after LT has not always been trast, in terms of survival, Borentain et al. found observed. Saks et al. evaluated retrospectively the that concomitant SPSSs were associated not only outcomes of patients undergoing LT with nonli- with the appearance of HE, but also with an gated splenorenal shunts, finding that their pres- increased risk of early mortality after TIPS.108 ence was not associated with post-LT mortality or However, the follow-up was limited to the first graft failure, compared with cirrhotic patients with- 30 days after TIPS placement. More evidence is out shunts.44 Despite no ligation being performed, needed to obtained solid conclusions. almost half of the evaluated shunts spontaneously decreased in size after LT. In the recent study per- formed by Rodrígez et al., in which the majority of SPSSs and influence after liver SPSSs were not ligated (only five large SPSSs from transplantation a cohort of 263 shunts), SPSSs did not influence The clinical impact of SPSSs in LT is still a mat- graft survival or patient survival, regardless of the ter of debate. Previous studies have reported that size of the collateral and the type of graft used (car- large SPSSs are associated with increased rate of diac-death donation or brain-death donation).33 complications after LT when left untouched, including primary nonfunction and disfunction of To summarize, the management of SPSSs in LT is the graft, higher risk of portal vein thrombosis still controversial. Current recommendations sug- and reappearance of HE.110–112 These complica- gest considering the ligation of SPSSs in high-risk tions are thought to be driven by the diminished patients with low portal venous flow or very large irrigation to the graft, as part of the flow circulates shunts, to avoid graft hypoperfusion, portal com- through the shunt, causing a “portal steal” phe- plications or HE. However, in small-sized grafts nomenon.113 Thereby, SPSS ligation during LT and technically difficult scenarios, SPSSs should surgery has been proposed and successful short- not be ligated. During long-term follow-up, in case term outcomes reported.114 However, there are of persistence of symptomatic large SPSSs, shunt concerns about procedure-related complications, embolization could be considered, although the such as bleeding or inferior vena cava thrombosis. experience in embolization after LT is extremely In the study performed by Gómez-Gavara et al. limited, documented as isolated case reports.87,116 consecutive patients with splenorenal shunt >1 cm were included and approximately half of them had the shunt ligated during surgery.45 In Conclusion the remaining patients the shunt was left in place, In conclusion, SPSSs are very frequent in patients according to a clamping test performed during with cirrhosis their prevalence increases as liver the surgery, which consisted of checking whether function deteriorates, and represent an indirect the hepatic portal flow improved or not after indicator of severe PH. Furthermore, their pres- clamping the shunt. Interestingly, SPSS ligation ence has been related to worse prognosis, espe- during LT was associated not only with less post- cially in patients with preserved liver function. operative morbidity, HE and portal vein throm- SPSSs may identify a subgroup of patients with bosis, but also with better patient and graft good liver function but advanced PH, thus more long-term survival during a mean follow-up of likely to develop complications. Large SPSSs are 25 months. Recently, Alland et al. have observed frequently found in patients with persistent and in recipients of living-donor LT that portal vein recurrent HE, being a useful therapeutic target in thrombosis and size of splenorenal shunt, previ- selected cases. Similarly, patients with liver cir- ous to LT, were predictors of portal complica- rhosis candidates for TIPS with concomitant tions (defined as portal stenosis, thrombosis or large SPSSs, may benefit from simultaneous hepatofugal flow, requiring surgical, percutane- embolization to avoid post-TIPS HE. Finally, the ous or medical management); in particular, portal management of SPSSs in LT is still controversial, vein thrombosis and splenorenal shunt diameter considering the ligation of large SPSSs to avoid <8 mm led to a risk of portal complications of graft hypoperfusion a possible intervention. 8.3%, which increased to 16.7% when shunt diameter was 8–15 mm and to 38.5% with diam- Conflict of interest statement eters >15 mm. The authors proposed to consider The authors declare that there is no conflict of intraoperative intervention in these cases.115 interest. journals.sagepub.com/home/tag 13 Therapeutic Advances in Gastroenterology 13 Funding 8. Acharya C and Bajaj JS. Altered microbiome in The authors disclosed receipt of the following finan- patients with cirrhosis and complications. Clin cial support for the research, authorship, and/or Gastroenterol Hepatol 2019; 17: 307–321. publication of this article: Judit Vidal-González is a 9. Tarantino G, Citro V, Esposito P, et al. Blood recipient of a PFIS grant (FI19/00330) from ammonia levels in liver cirrhosis: a clue for the Instituto de Salud Carlos III, Spain. Macarena presence of portosystemic collateral veins. BMC Simón-Talero is a recipient of a Juan Rodés grant Gastroenterol 2009; 9: 21. JR 17/00029 from Instituto de Salud Carlos III, 10. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic Spain. Joan Genescà is a recipient of a Research encephalopathy in chronic liver disease: 2014 Intensification grant from Instituto de Salud Carlos practice guideline by the American Association III, Spain. The study was partially funded by grants for the Study of Liver diseases and the PI18/00947 from Instituto de Salud Carlos III and European Association for the Study of the Liver. co-funded by European Union (ERDF/ESF, Hepatology 2014; 60: 715–735. “Investing in your future”). Centro de Investigación 11. American Association for the Study of Liver Biomédica en Red de Enfermedades Hepáticas y Diseases and European Association for the Digestivas is supported by Instituto de Salud Carlos Study of the Liver. Hepatic encephalopathy in III, Spain. chronic liver disease: 2014 practice guideline by the European Association for the Study of ORCID iD the Liver and the American Association for the Macarena Simón-Talero https://orcid.org/0000- Study of Liver Diseases. J Hepatol 2014; 61: 0002-1409-3936 642–659. 12. Rössle M. TIPS: 25 years later. J Hepatol 2013; 59: 1081–1093. References 13. Bandali MF, Mirakhur A, Lee EW, et al. Portal 1. Nardelli S, Riggio O, Gioia S, et al. 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