Chronic liver disease is an adult major disorder worldwide (1). There are many etiologies of chronic liver disease, viral hepatitis [hepatitis B virus (HBV) or hepatitis C virus (HCV)], alcohol abuse, primary biliary cholangitis, nonalcoholic steatohepatitis, and autoimmune hepatitis (2-6). However, irrespective of the reasons, the end stage is cirrhosis, which shows risk factors for developing hepatocellular carcinoma, and other complications such as ascites, icterus, gastroesophageal varices and hepatic encephalopathy (7-9).
Portal hypertension is a principal pathophysiology of cirrhosis and noncirrhotic portal hypertension (10). It is defined by the elevation of portal pressure, hepatic venous pressure gradient (HVPG) >5 mmHg (11). An HVPG of 10 to 12 mmHg is the threshold level for the development of esophageal varices (EV), ascites, and the occurrence of variceal bleeding (10,12), and an HVPG higher than 16 mmHg suggests an increased risk of death (13,14). Surgical resection of large malignant tumors (major liver resections) is generally contraindicated in patients with portal hypertension (15,16). Moreover, an HVPG higher than 20 mmHg is the best independent prognostic marker for acute variceal bleeding (17-20) and thus indicates the presence of a much more severe status. The underlying mechanism of portal hypertension is the increased intrahepatic vascular resistance caused by hepatic fibrosis and/or the increased portal venous flow due to the elevated splanchnic blood flow (21-24). Splenomegaly caused by portal hypertension also accounts for the elevation of portal venous flow.
The development of collateral vessels is a characteristic feature of impaired portal hemodynamics. The paraumbilical vein (PUV), left gastric vein (LGV), posterior gastric vein (PGV), short gastric vein (SGV), splenorenal shunt (SRS), and inferior mesenteric vein (IMV) are major collaterals, and there are some rare collaterals. Each individual has their own pattern, single or combination of multiple collaterals. Imaging modalities, such as ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are used for detection and grading. The degree and hemodynamics of the collateral may affect the portal venous circulation and may compensate for the balance between inflow and outflow volume of the liver. Furthermore, the development of the collateral shows a relation with the liver function reserve, and clinical manifestations such as EV, gastric varices, ectopic varices, hepatic encephalopathy and/or prognosis. Thus, the assessment of collaterals may enhance the understanding of the underlying pathophysiology of the condition of patients with portal hypertension. This review article focuses on the anatomy, clinical relevance and interrelationship of collateral vessels (except for cavernous transformation of the portal vein), summarizes the current concept and discusses the future directions of the research.
The PUV is a vessel in the falciform ligament that has been used as a fetal circulation. It develops at the hepatic surface side of the umbilical portion of the intrahepatic left portal vein and goes to the extrahepatic area, running toward the iliac vein (Figures 1,2). Almost one-third of the patients with the peri-umbilical collateral have multiple, not single vessels in the cohort of portal hypertension (25). The caput medusae is a unique appearance seen radiating from the umbilicus across the abdomen via epigastric veins. Dilatation of these abdominal veins could be observed in patients with severe portal hypertension through distended and engorged PUVs. However, it may also be present in clinical conditions such as inferior vena cava syndrome or superior vena cava syndrome with obstruction of the azygous system.
The incidence of a patent PUV has been reported to be 11.1% (26), 15.6% (27), 26% (28), 33.7% (29), and 42% (30) in adult cirrhotic patients. Also, the studies demonstrated the increased flow volume in the portal trunk, which is the different point from the patients with extrahepatic collaterals. Although the reduced portal flow and advanced extrahepatic collaterals are reported as significant factors for developing portal vein thrombosis (31,32), the substantial effect of PUV for the suppression of portal vein thrombosis remains to be elucidated.
Investigators have shown the close relationship between the presence of patent PUV and worse liver function (27,29). A more recent study reported that the mean flow volume in the portal trunk, incidence of the LGV with hepatofugal flow direction and the grade of EV were significantly higher in patients with a patent PUV (908.2 mL/min; 70.2%; and 9 with none to small vs. 27 with medium to large, respectively) than in those without (771.7 mL/min; 48.5%; and 57 with none to small vs. 48 with medium to large, respectively) (28). The HVPG and wedged hepatic venous pressure (mmH2O) were significantly higher in the former (268.0±89.7 and 389.5±99.9, respectively) than in the latter (203.5±63.2 and 317.7±67.7, respectively). Furthermore, the deterioration of ascites in the 2-year period was significantly more frequent in patients with a patent PUV (4/12, 33.3%) than in those without. The published data strongly suggest that a patent PUV appears to be a sign of pressure-loaded portal hemodynamics in cirrhotic patients. Although a patent PUV may result in an underestimation of the degree of portal hypertension because of less reduction of portal trunk blood flow, the clinician needs to be aware of the worse condition of the patients.
The LGV runs in the small omentum along the lesser curvature of the stomach, showing a coronary shape, and connects to the portal system at the portal splenic angle, portal trunk or splenic vein. Thus, clinically, the LGV and the coronary vein are treated as equivalent. It shows close connection with systemic circulation at the esophagogastric junction and/or around the esophagus through the azygos vein or accessory hemiazygos vein.
A recent clinical study in 1,325 patients with gastric cancer who underwent radical resection analyzed the intraoperative vascular anatomy and reported five types of LGV drainage patterns: type 1 with the LGV passed to the ventral side of the splenic artery and common hepatic artery in 743 patients (56.1%), type 2 with the LGV at the dorsal side of the common hepatic artery in 550 patients (41.5%), type 3 with the LGV at the dorsal side of the splenic artery in 4 patients (0.3%), type 4 with the LGV along the hepatogastric ligament, draining directly into the liver in 21 patients (1.6%), and type 5 with the negative LGV and the right gastric vein was enlarged in 7 patients (0.5%) (33). Endoscopic ultrasonography (EUS)-based analysis has demonstrated the detailed anatomy of the peripheral branching in patients with portal hypertension; LGV bifurcates into anterior and posterior branches, the former goes to EV (Figures 1,3) and the latter goes to the paraesophageal vein (Figures 1,4) (34). However, as the study was performed in cases with gastric cancer, it should be noted that the anatomical feature may not necessarily be applied to the patients with portal hypertension.
The LGV shows hepatopetal flow direction in the normal subjects, as the role is to collect the blood flow from the upper stomach and to drain it into the portal system (Figures 1,5). However, in cases of portal hypertension, the flow direction of the LGV changes in a hepatofugal manner, and the LGV acts as a major pathway that brings portal blood flow into the EV and/or paraesophageal vein via the upper stomach (35). Therefore, it is the vessel which is present in healthy people as well as patients with portal hypertension.
Transabdominal US examination has shown 89.6% detectability of the LGV in cirrhosis patients with EV, and 87.6% of the LGV showed hepatofugal flow direction (36). Furthermore, the positive detection of the LGV showed 100% sensitivity and negative predictive value (NPV) to identify large EVs. The best cutoff value in the LGV diameter was 5.35 mm to identify large EVs, showing an area under the receiver operating characteristic curve (AUROC) of 0.753 with 90% sensitivity and 96.5% NPV.
The study performed earlier reported that the velocity in the LGV by transabdominal Doppler US was associated with the development of EV and bleeding risk (37). In the study using EUS, the branch pattern of the LGV was more likely to be anterior branch dominant (P=0.041), according to the enlargement of the variceal size (34). Additionally, another EUS-based study has shown lower hepatofugal flow velocity in the LGV trunk and a lower incidence of the anterior branch dominant type in therapeutic responders (38). These data strongly suggest the close linkage between LGV hemodynamics and the degree of EV and, therefore, US-based assessment (transabdominal/EUS) of the LGV is important in the noninvasive evaluation of the clinical severity of EV.
The LGV with hepatofugal flow direction also affect the development of hepatic encephalopathy, due to an aspect of portosystemic shunt, with or without creating EV (39-42). However, an actual incidence and clinical influence of LGV-related encephalopathy remains undetermined.
The portal hemodynamic response caused by vasoactive substances is another target of clinical research in patients with EV. A unique study using intravenous injection of glucagon (1 mg), which is known as a causative or modulating factor of splanchnic hyperemia in portal hypertension and chronic liver diseases (43), reported that an increase in flow velocity in the LGV that is due to glucagon depends on the degree of EV (44). Furthermore, a blunted response to vasoactive substances seems to be a hemodynamic feature of the LGV in patients with large EV and advanced portal hypertension, suggesting an implication for the mechanism of vasoactive substances in patients with portal hypertension and EV. Whenever there is grade 4 portal vein thrombosis (complete thrombosis of portal vein and proximal and distal superior mesenteric vein) and this is not accompanied by a large SRS, but the LGV is very large, the portal vein of the liver allograft may be anastomosed to the LGV of the recipient (45).
The PGV is the collateral situated between the LGV and the SGV, originating from the middle of the splenic vein (Figures 1,6), and runs posteriorly along the stomach wall. It drains into the EV (81%) and into the left renal vein (23%) in patients with portal hypertension (46).
The portogram-based study reported a 42% relative incidence of PGV in patients with portal hypertension, with forming communication to the left renal vein in 23% of cases (46). It showed a close relationship with the presence of EV (81%), gastric varices (23%), and the presence of hepatic encephalopathy (23%) (46). However, the physiological hemodynamics and clinical relevance of PGV remain to be elucidated because no study using Doppler US has been performed, probably because of the difficulty of detection by US.
The SGV is a collateral (usually including multiple vessels) that develops at the splenic hilum. It runs traversing the gastrosplenic ligament and drains the fundus and the left part of the greater curvature of the stomach.
A previous study performed on percutaneous portography reported the relative frequency of collaterals in patients with portal hypertension, SGV with 34% incidence following LGV with 90% and PGV with 42% (46). A study using US in cirrhosis patients reported an 86/233 (36.9%) incidence of SGV (corresponding to shunt vessel that runs cranial side), whose mean diameter was 6.4±2.3 (range, 2.6–13.1) mm and flow velocity was 11.2±6.7 (range, 4–44.1) cm/s (47). There is a close relationship between the presence of gastric fundal varices and SGV [44/86 (51.2%) with gastric varices] (Figures 1,7) (47), and the hemodynamics on Doppler US may be predictive of risky gastric varices; diameter, flow velocity and flow volume of SGV were significantly greater in bleeders (9.6±3.1 mm, 11.4±5.2 cm/s, 499±250.1 mL/min) than non-bleeders (6.5±2.2 mm, P=0.0141; 7.9±3.3 cm/s, P=0.022; 205±129.1 mL/min, P=0.0031) (48). In addition, the advanced hemodynamics in the SGV may affect the flow direction of the splenic vein, resulting in the non-forward (reversed or to-and-fro), which showed a higher cumulative bleeding rate (38.8% at 3 years, 59.2% at 5 years) than in patients with forward splenic vein flow (18.7% at 3 years, 32.2% at 5 years, P=0.0199) (48).
Since the SGV also has a role as a portosystemic shunt, there is a certain relationship between the presence of the SGV and hepatic encephalopathy (46,47,49,50). However, the incidence of hepatic encephalopathy seems lower in case with the SGV than that with the SRS (47).
The SRS is a collateral demonstrated at the splenic hilum, acting as a connection between splenic vein and left renal vein. For the collaterals at the splenic hilum, in general, the SRS is defined for shunt without creating gastric varices, and the SGV is defined for that with creating gastric varices (47).
The relative incidence of SRS is reported to be 7% in patients with portal hypertension by using portography (46) and 10.7% (all with hepatofugal flow direction) in cirrhosis by using transabdominal US (47).
The presence of SRS may enhance the risk of chronic hepatic encephalopathy (51). The study performed later also reported that the degree of hepatic encephalopathy was significantly worse in patients with collateral at the splenic hilum on the caudal side (almost SRS, P=0.0047) than in those with collateral at the splenic hilum on the cranial side (almost SGV) (47).
Another study performed in 153 cirrhosis patients showed that patients with hyponatremia (Na <135 mEq/L) had a significantly greater frequency of possessing an SRS (SRS; P=0.0068) (52). Additionally, serum sodium concentrations were significantly lower in patients with SRS than in those without SRS (P=0.0193). The cumulative survival rate was significantly worse in patients with both hyponatremia and SRS (20% at 1 year). These data strongly suggest the negative influence of SRS on the liver function reserve and prognosis in cirrhosis. Whenever there is complete obstruction of the portal vein by thrombosis, every attempt should be performed to accomplish complete removal of the thrombus. Whenever there is grade 4 portal vein thrombosis (complete thrombosis of portal vein and proximal and distal superior mesenteric vein) and this is accompanied by a large SRS, the left renal vein may be ligated next to the confluence with the inferior vena cava and a renoportal bypass using a venous graft may be created to perfuse the portal vein of the liver allograft during liver transplantation surgery (53-55).
The IMV is the vessel that runs anterior to the sacrum and toward the upper abdomen, passing posterior to the distal duodenum and anterior to the left renal vein and the superior mesenteric artery before communicating with the portal system. The main route in the portal system for which the IMV drain is the splenic vein (Figures 1,8), followed by the superior mesenteric vein or the splenomesenteric confluence. The distal area whose blood flow is covered by IMV is from the distal transverse colon to the proximal rectum (56). Actually, it has often been used as a route to decompress portal pressure by surgical treatment (57).
Peripheral branches of the IMV with hepatofugal flow direction are closely related to the development of rectal varices, characterized by the collaterals between superior rectal veins and middle to inferior rectal veins of the iliac venous route. The incidence of rectal varices is 35% to 59.9% in cirrhosis and 89% in noncirrhotic portal hypertension, depending on the patient population (61-65).
There seems to be no relationship between Child’s grade, the grade of EV, the presence of gastric varices, portal hypertensive gastropathy, or whether patients received sclerotherapy and the development of anorectal varices (65). The HVPG of cirrhotic patients with anorectal varices was similar to that of cirrhotic patients without anorectal varices (14±6 mmHg, n=22, vs. 16±7 mmHg, n=39, P>0.05). Additionally, the prevalence of anorectal varices in cirrhotic patients had no relation to ascites (64). The presence of the red sign on rectal varices may suggest a high-risk condition for bleeding; however, the detailed pathophysiology of bleeding risk has not been clarified (66).
A more recent clinical study performed in 467 cirrhosis patients demonstrated hemodynamics in the IMV using Doppler US; 20.1% detectability of IMV showed hepatopetal flow in 51, hepatofugal flow in 33 and to and fro in 10 (67). Patients with IMV with hepatofugal flow showed more severe ascites (P=0.006), more severe Child’s grade (P=0.004), higher incidence of decompensated condition of the liver (17/33, 51.5% vs. 14/51, 27.5%; P=0.015), and more frequent rectal varices (9/16, 56.3% vs. 2/15, 13.3%; P=0.013) than the patients who had IMV with a hepatopetal flow direction. However, the incidence of gastroesophageal varices was lower in patients who had IMV with hepatofugal flow (17/33, 51.5%; P=0.005) or to and fro (4/10, 40%; P=0.008) than IMV with hepatopetal flow (41/51, 80.4%) (67). The study suggested two opposite effects of IMV in cirrhosis: a deteriorating effect that promotes rectal varices and hepatic encephalopathy and an ameliorating effect that reduces the chance of gastroesophageal varices.
Other types of rare collaterals
Collaterals may rarely occur in the retroperitoneum, and duodenal varices are one of them, with an incidence of 0.4% in patients with portal hypertension (68). The duodenal varices present in the submucosal layer of the posterior wall of the duodenum with the superior/inferior pancreaticoduodenal vein originating in the portal vein trunk and/or superior mesenteric vein as the inflow route and the inferior vena cava as the outflow route (Figures 1,9). Although there are many treatment options using endoscopy, interventional radiology and surgical procedures, the definitive management direction of duodenal varices has not been determined (69).
Collateral which drains into the right renal vein (RRV)
Collateral drainages into the RRV is very rare, and there are only several case reports. The other side of the collateral is the portal vein (70,71) or superior mesenteric vein (Figures 1,10) (72-74). Severe liver function typified with chronic hepatic encephalopathy and/or ascites is the characteristic feature of the patients. Further investigation with a larger cohort may be needed to determine the actual incidence, clinical significance and appropriate management of this type of collateral.
Stomal varices is a relative rare condition, which account for 5% of variceal bleeding (75). The most common story may be the occurrence in patients with ileostomies after proctocolectomy for inflammatory bowel disease with associated primary sclerosing cholangitis. As with the other varices, it is related to the collateral development, branch of superior mesenteric vein (76), or that of IMV (77), in post-colectomy patients with portal hypertension. It is considered as a treatment resistive condition because the threshold portal pressure gradient leading to bleeding may be lower than for EV or gastric varices (78).
Comprehensive discussion and future prospective
Reopening of the embryonic venous channel and spontaneous shunt
There is no report regarding the presence of the following collaterals in normal subjects: PUV, SRS, PGV, and SGV; therefore, the detection of these vessels may suggest the presence of portal hypertension. However, the LGV and the IMV are vessels that are also present in normal subjects. A previous study using Doppler US reported the presence of LGV with hepatopetal flow direction in 39 healthy adults (37). For the IMV, the diameter measured behind or to the left of the duodenojejunal flexure was 3–6 mm (mean ± standard deviation, 3.9±0.83 mm) in 14 normal cases (79), and portal hypertension was suggested when the diameter of the IMV was 9 mm or more. Anatomy of the IMV in normal subjects is well described by multidetector CT (80), and the IMV with hepatopetal flow direction by Doppler US in normal subjects is clearly demonstrated (56). Therefore, in a precise sense, an identification of the LGV or the IMV as the collateral caused by portal hypertension may be determined by the assessment of flow direction in the vessels, and Doppler US may be an essential tool for this purpose with the possible evaluation of physiological hemodynamics. Furthermore, these two collaterals may not be classified as spontaneous shunts when they are defined by the reopening of the embryonic venous channel.
Influence of collateral on the intrahepatic blood flow or other collaterals
Development of collateral provides steal of blood flow which should be into the liver, and this phenomenon accounts for the worse condition of the patients. The negative influence may be explained by the improved shunt patency of transjugular intrahepatic portosystemic shunt by adding coronary vein embolization (81). It is also supported by the data that the ligation of left renal vein to control SRS is effective even after liver transplantation (82,83). In addition, the improvement of hepatic encephalopathy after the embolization of collateral with balloon-occluded retrograde obliteration may enhance the benefit of the control of collateral hemodynamics in patients with portal hypertension (49,84).
Meanwhile, the development of collaterals may affect the hemodynamics of other collaterals, resulting in changes in clinical manifestations.
For the development of varices, the presence of an SRS may have a role in suppressing the formation of gastroesophageal varices but without reducing the risk of bleeding. Similar data are reported in the study regarding IMV; the incidence of gastroesophageal varices was lower in patients who had IMV with hepatofugal flow or to and fro than IMV with hepatopetal flow (67).
However, there is an argument that there is no significant relationship between the presence of SRS and degree/bleeding of EV (85) and no difference in the incidence of rectal varices between cirrhosis patients with and without EV (65). Meanwhile, it has been reported that a large EV was detected more frequently in patients with SRS than in those without SRS (86), and a higher incidence of LGV with hepatofugal flow direction and grade of EV was demonstrated in patients with a patent PUV (67). Therefore, the interrelation influence between different collaterals may depend on the type, pattern and degree of collaterals.
Summary of imaging techniques for the evaluation of portal system and collaterals
There are many imaging modalities to assess the hemodynamics in the portal system and collaterals (Table 1). Firstline approach may be, undoubtedly, US with the advantage of almost no invasiveness and real-time observation. However, operator-, and patient-dependency may be linked to the low reproducibility and objectivity of US, while CT/MRI may have the advantage in this regard. A major indication of US, CT, and MRI to assess the hemodynamics of collateral is to detect blood flow, to evaluate the flow direction, and to measure the velocity/flow volume by using Doppler US method.
Interventional technique using catheter may provide more detailed investigation; portogram by arteriography, hepatic venous catheterization and percutaneous transhepatic portography (PTP). The latter two methods may be the standard for the assessment of portal hemodynamics, the former for HVPG and the latter for direct measurement of portal pressure. The real-world indication of these procedures may be therapeutic support except for research purpose, arteriography for partial splenic embolism, hepatic venous catheterization when performing balloon-occluded retrograde obliteration, and PTP for portal obstruction.
As for the advanced technology, share wave elastography (possible evaluation of liver/spleen stiffness with real-time observation even in patients with ascites), which is available for noninvasive prediction of the severity of portal hypertension and EV (87-89). However, it is an indirect assessment and lower specificity may be the disadvantage. Xenon CT shows quantitative assessment of hepatic tissue blood flow as well as arterial/portal venous flow (90). Four-dimensional flow MRI is also available to evaluate portal hemodynamics by using volumetric acquisition technique (91-93). However, time/spatial resolution and simplicity are not satisfactory with CT/MRI, which may be hard to be used as a common tool. Taken together, ideal imaging tool may not be present at this time, and multiple modalities need to be selected according to the patient condition and the availability of the adequate resources and expertise.
Future direction of the research for collaterals
Based on the analysis with a specific single collateral vessel, there seems to be no linkage between the prognosis and the development of collateral, PUV (28), SRS (52) and IMV (67). However, a recent clinical study including 1,729 patients reported the relationship between poor prognosis and the development of collateral (irrespective of the kind of collateral) (94). The underlying pathophysiology related to the unfavorable outcome of patients with collaterals needs to be clarified, and additional studies are necessary to determine whether intervention for collateral embolization may have a survival benefit (95). Another aspect is the paucity of the data regarding the role and influence of collaterals in the early stage of portal hypertension. Furthermore, criteria and optimal imaging modality to determine the severity of collaterals should be discussed for the standard assessment.
Each collateral has a specific function depending on the anatomy and hemodynamics and is linked with the relative clinical presentation in patients with portal hypertension. Imaging modalities may be essential for the detection, grading and evaluation of the role of collaterals and may help to understand the pathophysiology of the patient condition. Further investigation in a large-scale study would elucidate the basic and clinical significance of collaterals in patients with portal hypertension and may provide information about how to manage them to improve the prognosis as well as quality of life.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-20-1328). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This article does not contain any studies with human participants performed by any of the authors.
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