The Hepatic Fetal Venous System

Abstract

The vascular architecture of the human liver is established at the end of the 10th week of gestation as a result of a complex process. Recent developments in ultrasonographic imaging facilitate the prenatal evaluation of this system. However, many of the involved mechanisms are poorly understood. The hepatic primordium is in contact with the vitelline veins and the umbilical veins, and by the end of the 6th week, the afferent venous system of the liver is acquired giving rise to the portal vein, the portal sinus, and the ductus venosus. The only afferent vein of the liver that remains open at birth is the portal vein. Also, the efferent venous system of the liver is formed and emerges from the vitelline veins.

1. Introduction

Intensive research has been done in the evaluation of the fetal venous system to recognize the normal and abnormal sonographic appearance. Furthermore, prenatal diagnosis of fetal venous system anomalies requires knowledge of its embryology and physiology. The information currently available regarding the etiology, importance, and prognosis of these abnormalities enables caregivers to provide appropriate parental counseling when an anomaly is encountered. Still, the sonographic evaluation of the fetus’s venous system remains largely undetermined and needs more studies.

2. Fetal circulation

The fetal circulatory system functions differently than after birth and has certain properties that are present only prenatally and are very important since the fetus is completely dependent on the mother’s circulation. Thus, ductus arteriosus, ductus venosus, foramen ovale, and placental-umbilical flow are vital to fetal life. The placenta oxygenates the deoxygenated blood, and the three shunts allow umbilical blood to bypass specific organs (liver and lungs). As a result, oxygenated blood is delivered via the umbilical vein (UV) to the liver (70–80%) and directly to the fetal heart, across the DV (20–30%).

Roughly 60% of the fetal cardiac output is pushed through the umbilical arteries and back to the placenta. The placenta’s blood returns to the fetus via the umbilical vein, which has an oxygen saturation of about 80%. The DV rises from the umbilical and portal system connection, as a continuation of the UV, bypasses the liver, and joins the inferior vena cava at the level of sinus venosus, located at the base of the right atrium. Although DV oxygenated flow joins venous blood from the lower trunk and extremities, as well as blood from the liver, because of the DV direction and flow velocity, it is preferentially directed from the right into the left atrium via foramen ovale.

The UV, DV, foramen ovale, left atrium and ventricle, and the aorta form the so-called via sinistra, while the superior and inferior vena cava, the right atrium and ventricle, the pulmonary artery, and the ductus arteriosus form the via dextra. The majority of blood from the superior vena cava enters the right atrium and ventricle and exits via the pulmonary artery.

Because the collapsed lungs have high resistance and the pressure in the pulmonary artery is higher than in the aorta, most of the blood in the pulmonary artery travels via the ductus arteriosus to the descending aorta. The fetus’s head receives better-oxygenated blood from the left ventricle and aortic arch [1].

3. Fetal venous system – embryology

The vascular architecture of the liver is very complicated, and understanding the embryology and pathophysiology of the fetal venous system is critical for a more effective approach.

The cardiovascular system is the first organ system to develop. In a 4-week embryo, three symmetric paired veins flow to the right and left horns of the sinus venosus into the heart: the umbilical veins (UVs)−which drain the chorion, vitelline veins (VVs)−which drain the yolk sac, and cardinal veins (CVs)−which drain the embryo’s body.

The septum transversum development of the fetal liver allows the connection of the vitelline and umbilical veins with the sinusoids, resulting in changes in the VVs and UVs: the left UV becomes the dominant pathway of blood from the placenta, while the right UV and the left cranial segment of the left UV become atrophic and disappear. The left umbilical vein receives practically all of the placental blood drainage and will route itself through the hepatic sinusoids that develop from the vitelline veins [1, 2].

A large channel develops and shunts blood from the left umbilical vein to the right cardiac channel and then to the sinus venosus. This is ductus venosus, the functional shunt that allows oxygenated placental blood to bypass the liver, with a relatively direct path to the heart. The establishment of a DV as a “critical anastomosis” between the umbilical and vitelline venous systems, followed by increased hepatic perfusion, appears to be important for the successful development of an intrahepatic portal venous system.

The growing sinusoids, on the other hand, will form the right and left hepatic veins, which will all drain to the developing inferior vena cava, at the site of the right cardiac channel. The primitive vitelline veins create the future portal venous system within the liver. The vitelline veins will degenerate proximally on the left side, and more distally on the right side, resulting in a convoluted S-shaped path along the back and front of the growing gut. Around the same period, the superior mesenteric vein and the splenic vein will develop from the VVs, and eventually converge to form the hepatic portal vein.

The common cardinal veins, with anterior and posterior cardinal veins draining the embryonic cranial and caudal segments of the embryonic body, comprise the third venous system that enters the sinus venosus. The posterior branches of the CVs are severed, but the caudal portion remains, giving birth to the common iliac vein and the caudal part of the IVC. The CVs are eventually replaced by subcardinal veins, which drain the kidney and gonads, and supracardinal veins, which drain the thoracic wall and iliac veins.

The superior portion of the left supracardinal vein obliterates and joins to the right branch, establishing the renal–hepatic segment of the IVC. The inferior portion of the left supracardinal vein obliterates and connects to the right subcardinal vein, forming the sacrorenal segment of the IVC. The superior segment of the supracardinal vein is divided into two branches: the left branch, known as the hemiazygos vein, which forms a cross anastomosis with the right branch, known as the azygos vein, which drains into the superior vena cava.

The proximal left anterior CV recedes and separates from the sinus venosus. During the eighth week, the left brachiocephalic vein develops from the shunt produced to the right anterior CV. Meanwhile, the SVC develops from the confluence of the left and right brachiocephalic veins and the right atrium.

Afferent and efferent venous networks form inside the developing fetal liver. The afferent system consists of the UV, PV, and DV, whereas the efferent system consists of the hepatic veins.

An invagination of the left atrium dorsal wall is visible in the 4-mm embryo, which represents the developing common pulmonary vein. The connection process continues as the atrial cavity grows, and two right and two left branches of the pulmonary stem become connected with the atrial cavity. The pulmonary venous plexus loses its connection to the VVs and CVs throughout time (Figure 1) [1, 2, 3].

Figure 1.

Embryological development of the human venous system. A: The embryo demonstrates the development of paired sets of “vitelline” and “umbilical” veins in its fourth week, which initially drain the yolk sac and allantois. B: At the 4th week, there are three symmetric paired veins: the umbilical veins, vitelline veins, and cardinal veins. All three systems converge into the sinus venosus. C: In 5–8 weeks, the liver cords develop into the septum transversum and interrupt the cranial portion of the umbilical and vitelline veins. D: Asymmetric stage with the intrahepatic anastomosis developing between the umbilical-portal and ductus venosus systems. E: Changes in the VVs and changes in the UVs continue. Only the most caudal and the most cranial segments of VVs will persist. F: By the end of the 10th week, small venous branches, named venæ advehentes, convey the blood from the subhepatic anastomosis to the sinusoidal plexus; small venous vessels, named venæ revehentes, drain the blood of the sinusoidal plexus into the subdiaphragmatic anastomosis. SV: sinus venosus, VV: vitelline veins, PL: primordial liver, UV: umbilical veins, PCV: posterior cardinal veins, ACV: anterior cardinal veins, RUV: right umbilical vein, LUV: left umbilical vein, RVV: right vitelline vein, LVV: left vitelline vein, ARCV: anterior right cardinal vein, ALCV: anterior left cardinal vein, DU: duodenum, PS: portal sinus, IDA: intermediate dorsal anastomosis, CVA: caudal ventral anastomosis, PRCV: posterior right cardinal vein; PLCV: posterior left cardinal vein; RHCC: right hepatic common cardinal vein; IVChcs: inferior vena cava hepatocardiac segment; RPV: right portal vein; LPV: right portal vein; UV: umbilical vein; MPV: main portal vein; LP: liver parenchyma; IVC: inferior vena cava; PV: portal vein; MV: mesenteric vein; RA: ramus angularis; RTHV: right terminal hepatic vein; MTHV: median terminal hepatic vein; LTHV: median terminal hepatic vein; HCV: hepatic cardialis venula; OPVR: obliterated portion of venous rings; BD: bile duct; P: pancreas; VA: venae advehentes; VR: venae revehentes; ADPUV: anterior detached portions of umbilical vein. Images and legend from the collection of Dr. Anca-Maria Istrate-Ofiţeru, with permission.

4. Anatomy of the hepatic venous system

Although ultrasound imaging of the fetal venous system has improved, the ability to understand its anatomy and the true anatomical relationships of the portal venous system have not been clearly defined. Within the liver, there are two venous systems: an afferent and an efferent system. The efferent system includes the hepatic veins, which conduct blood from the liver to the heart, and the afferent system includes the portal system, which delivers the blood from the gut and placenta to the liver − through the UV. Thus, the umbilical system that carries blood from the placenta to the liver is part of the hepatic afferent venous system (Figure 2).

Figure 2.

Schematic representation of the afferent and efferent systems of the fetal liver.

The extrahepatic portal vein, also known as the main portal vein, results from the confluence of splenic and superior mesenteric veins. It travels behind the duodenum and empties into the portal sinus near the right intrahepatic portal vein’s origin. The right portal vein has two branches, anterior and posterior, while the left portal vein has three branches: inferior, middle, and superior. The portal sinus is an L-shaped vascular region that spans from the inferior left portal vein’s origin to the right portal vein’s origin. As a result, it joins the right and left intrahepatic portal veins, which perfuse the right and left hepatic lobes, respectively (Figure 3).

Figure 3.

The normal aspect of the portal venous system (PVS) and hepatic veins. (A) Transverse plane of the fetal abdomen demonstrating normal aspects of the efferent hepatic system: the left, middle, and right hepatic veins. (B) Axial plane of the fetal abdomen with the evaluation of the umbilical vein and left portal vein branches. (C) Transverse plane with the demonstration of the normal right portal vein and its branches. (D) STIC HD-flow evaluation of the afferent system of the liver. UV, umbilical vein; Ao, aorta; IVC, inferior vena cava; St, stomach; MPV, main portal vein; PS, portal sinus; RAPV, anterior branch of the right portal vein; RPPV, the posterior branch of the right portal vein; LiPV, left portal vein inferior branch; LmPV, left portal vein medial branch; RHV, right hepatic vein; LHV, left hepatic vein; MHV, middle hepatic vein.

The angle of communication at the confluence of the major portal vein and the portal sinus varies from 900 to a virtually parallel course. There are three types of connections between the main portal vein and the portal sinus: T-shaped, end-to-end anastomosis, X-shaped, side-to-side anastomosis, and H-shaped, parallel anastomosis. The majority of the blood flowing via the main portal vein is delivered to the right hepatic lobe [3].

According to Rudolph et al., portal blood is directed only to the right hepatic lobe, but umbilical venous blood nourishes both hepatic lobes and the ductus venosus. When compared to the left vein, the right portal vein receives less oxygenated blood. As a result, the left lobe is considerably larger than the right lobe throughout fetal life, a circumstance that is reversed after birth when the UV and DV become atrophic. The efferent venous system is made up of three hepatic veins: the right, middle, and left hepatic veins. These veins open to the subdiaphragmatic vestibulum and drain hepatic venous blood into the right atrium [4].

The umbilical vein enters the abdomen within the falciform ligament and joins the liver along its inferior surface, cephalic directed, and opens in the portal sinus, which is aligned with the arising ductus venosus. DV appears as a trumpet-like thin shunt with a diameter that is approximately one-third the diameter of the UV, which determines high blood velocities. Also, the DV direction connects with the right atrium pointing more posterior and cranial toward the foramen ovale (Figure 4). These are the reasons why there is a preferential flow of oxygen- and nutrient-rich blood from the placenta to the left atrium via the UV and DV [5].

Figure 4.

Macroscopic and ultrasound evaluation of the fetal liver. (A and B) Pathology examination shows the normal extrahepatic (A) and intrahepatic (B, liver tissue removed) pathway of the umbilical vein. (C) Longitudinal plane of the fetal abdomen, Color Doppler evaluation, showing the normal intrahepatic pathway of the umbilical vein and the normal aspect of the ductus venosus. (D) Longitudinal plane of the fetal abdomen, 3D rendering, which demonstrates the normal aspect of the afferent and the efferent hepatic systems. UV, umbilical vein; Ao, aorta; IVC, inferior vena cava; St, stomach; RPV, right portal vein; HV, hepatic vein; UC, umbilical cord; UA, umbilical artery.

DV is essential for providing oxygenated blood to the left side of the heart and for the normal development of the intrahepatic portal venous system. The absence of DV causes aberrant hemodynamics because there is a “steal” effect with lower intrahepatic flow, which may result in the vitelline veins failing to transform into the portal system [6]. During pregnancy, umbilical venous blood passes via the portal sinus to nourish the right and left intrahepatic portal veins, as well as the DV. When the placental circulation stops and the ductus venosus closes, blood travels from the extrahepatic portal vein to the left intrahepatic portal veins, perfusing both liver lobes.

Both common iliac veins join together to form the inferior vena cava (IVC), which connects with the two renal veins along its path. The IVC is on the right side of the spine in the lower and mid-abdomen, and then it flows over the posterior liver surface to enter the right atrium.

5. Ultrasound assessment of the liver vasculature

By the end of the 10th week of gestation, the portal venous system (PVS) is already formed. However, due to the embryo’s size, ultrasonographic examination of this system is not possible. At the time of the standard first trimester (FT) anomaly scan (12–13 gestational weeks), the fetal portal venous system (PVS) architecture, as well as the presence of ductus venosus, can be analyzed [7, 8]. It has been also demonstrated that microscopic techniques could serve as an audit to assess the prenatal PVS features determined by first-trimester ultrasound assessment (Figure 5).

Figure 5.

The fetal liver’s macroscopic, microscopic, and ultrasonographic features. (A, B, C): Transverse planes at the level of PVS in the second trimester of pregnancy. (A) Color Doppler evaluation, (B) macroscopic evaluation, and (C) microscopic evaluation of the fetal liver, showing the hepatic course of the umbilical vein (UV), the L-shaped portal sinus (PS), the junction of the PS with the main portal vein (MPV), the left portal vein, the right portal vein, and their branches. (D, E, F): First-trimester evaluation of the hepatic venous system. (D) Color Doppler evaluation of the portal venous system and (E) the normal aspect of the ductus venosus. (F) Microscopic demonstration of the portal venous system features. St: stomach, PS: portal sinus, MPV: main portal vein, UV: umbilical vein, LsPV: superior branch of the left portal vein; LiPV: inferior branch of the left portal vein; LmPV: middle branch of the left portal vein; RAPV: anterior branch of the right portal vein, RPPV: posterior branch of the right portal vein. Adapted from [7], Courtesy of Nagy et al., with permission.

Ultrasound examination of the embryonic venous system has shown a wide spectrum of abnormalities. This system’s aberrant development may be caused by defects in one of the four embryonic systems: the umbilical, vitelline, cardinal, or pulmonary systems. In most cases, venous malformations occur because the primitive veins do not undergo obliteration, or the development of crucial anastomoses does not occur. There has been proposed a novel classification of fetal venous system anomalies that expands on the four major embryonic groups mentioned above, but we will focus on the anomalies of the vitelline and umbilical systems [9].

5.1 Umbilical veins

5.1.1 Primary failure to create critical anastomoses, leading to abnormal UV connection with agenesis of ductus venosus (DV) and intra- or extra-hepatic systemic shunt of the UV

Agenesis of ductus venosus (ADV) occurs secondary to the absence of “critical anastomoses” between the portal and umbilical venous system and the hepatic–systemic venous system. This leads to the shunting of umbilical blood through an aberrant vessel. As a summary of the literature, in isolated ADV with intrahepatic UV drainage, the neonatal outcome is generally good but attention must be given to cases with intrahepatic shunts between the portal and hepatic veins concerning hyperammonemia and elevated liver enzymes that should be monitored after birth until the shunt closes. Also, in cases with extrahepatic UV drainage, it is important to monitor the closure of the shunt. In cases of ADV with extrahepatic shunt, the prognosis is determined by the severity of associated anomalies, the diameter of the shunt, and the development of the portal system [10]. In cases of isolated agenesis of the ductus venosus, the postnatal outcome depends on the persistence of a portosystemic shunt or agenesis of the portal venous system [11]. The association of the ADV with portal venous agenesis affects the long-term outcome due to severe postnatal complications, including congestive heart failure, pulmonary edema, focal nodular hyperplasia, and hepatic tumors [12, 13, 14].

5.1.2 Persistent right UV (PRUV) with or without left UV and/or DV

PRUV, an anomaly that results from the failure of the right umbilical vein atrophy, represents the most frequently detected fetal venous system anomaly. The left umbilical vein may be replaced or the RUV may be found as an intrahepatic vein, connecting to the right portal vein. Also, it may determine anomalous drainage of blood into the IVC or right atrium, bypassing the liver [15, 16, 17]. It has been suggested that primary or secondary occlusion by thromboembolic events arising from the placenta may lead to early streaming of blood through the right UV to cause this anomaly [18]. Echogenic foci situated within the fetal liver suggest this etiology. Ultrasound visualization of an aberrant vein passing laterally to the right of the gall bladder, in the plane of measurement of the abdominal circumference, is suggestive of PRUV. According to the reported data from the literature, in the absence of other anomalies, PRUV with normal DV connection usually represents a normal anatomical variant with no clinical significance [15, 19, 20].

5.1.3 UV varix

Umbilical vein varix is a focal dilatation of the vein, more often at the level of intra-abdominal UV, being diagnosed when a sonographically anechoic cystic mass is seen between the abdominal wall and lower liver edge, continuing the UV and with venous Doppler signal. The intra-abdominal UV varix has been defined as an intra-abdominal UV diameter at least 1.5 times greater than the diameter of the intrahepatic UV, or as an intra-abdominal UV diameter exceeding 9 mm [21]. Diagnosis of UV varix requests a detailed anatomical examination, karyotyping, echocardiography, and close monitoring of the fetus for sonographic signs of hemodynamic disturbance because of the high risk for unfavorable outcome [22].

The umbilical-portal-DV complex is a vascular unit, and each component can be affected. Abnormal communications of the portal, umbilical venous system, and hepatic-systemic venous system have been classified under the term “umbilical–portal-systemic venous shunts” (UPSVS). Three types of shunts have been previously reported: type I, umbilical-systemic shunt (USS), type II, ductus venosus–systemic shunt (DVSS), and type III, portal-systemic shunt, divided into type IIIa, intrahepatic portal-systemic shunt (IHPSS) and type IIIb, extrahepatic portal-systemic shunt (EHPSS). More recently, a new type of shunt has been reported, type IV, which includes multiple shunts of different types [23]. The outcome in UPSVS and ADV cases depends on the presence of concomitant structural or genetic abnormalities. Venous system anomalies can be accompanied by heart, digestive, and body symmetry abnormalities, known as left and right atrial isomerism.

5.2 Vitelline veins

Complete agenesis of the portal system (portosystemic shunt) or partial agenesis of right, left, or both portal branches (porto-hepato-systemic shunt)

Few cases of total or partial agenesis of the portal venous system have been reported during fetal life and apparently this anomaly is most likely underdiagnosed, but detection increases significantly with a systematic examination and the routine use of color Doppler is implemented. Lately, a classification of this condition has been proposed; there are two types of portal agenesis: type I (complete absence of portal venous system) and type II partial agenesis, which is further classified into IIa, IIb, and IIc, according to the shunting site [9, 24].

1. Complete absence of the portal venous system (CAPVS) occurs due to the failure of the vitelline veins to transform into the portal system, which also leads to a failure to form the critical anastomosis with the hepatic sinusoids or UVs. The splenic and superior mesenteric veins do not joint to form the portal vein or, if they form it, the drainage is done into the systemic circulation (IVC, renal vein, azygos vein, etc.). As a result, liver development is supplied by a compensatory increase in the hepatic arterial perfusion. The failure to form the critical anastomosis between the UV and the vitelline venous system seems to be the reason and the link between the agenesis of the DV and the agenesis of the portal venous system. Achiron et al. suggested that when ADV is detected, caregivers should rule out the presence of the total or partial agenesis of the portal venous system, and the splenic or superior mesenteric vein should be investigated for the presence of a triphasic pulsatile flow, which raises the suspicion of a portosystemic shunt [9]. Mesenteric and splenic venous blood may drain directly into the IVC, renal veins, or hepatic veins, or via the caput medusa to the heart. Isolated CAPVS is rare, as the frequency of associated major anomalies is high [12]. There have been reported heterotaxy–polysplenia cases, congenital heart disease (CHD) − atrial septal defect and/or ventricular septal defect, Goldenhar syndrome, and chromosomal anomalies.

2. Incomplete absence of the portal venous system (IAPVS) occurs due to a partial failure to form critical anastomoses. This is a more benign presentation of vitelline vein abnormality and with a better outcome, due to the rare association of other malformations and with a high chance of neonatal spontaneous resolution. The consequence of partial maldevelopment of critical anastomosis is agenesis of the right portal system, with a persistent left vitelline vein connected to the hepatic vein (portohepatic shunt) with or without the development of the DV. However, the intrahepatic shunt ratio may influence the hemodynamics with repercussions on the fetal growth − intrauterine growth restriction [25].

The decreased portal blood flow into the liver due to the hepatic bypass of the portal circulation increases blood flow in the hepatic artery − the so-called hepatic artery buffer effect.

Long-term metabolic sequelae of portosystemic shunting are often identified in retrospection and include hypergalactosemia, hyperbilirubinemia, hyperammonemia, and liver masses, including focal nodular hyperplasia, adenoma, hepatoblastoma, hepatocellular carcinoma, and rarely encephalopathy [10].

6. Conclusions

Abnormalities in the PVS are more likely to occur along with abnormalities of the ductus venosus due to the connections established during embryology. An important finding from previous research is that the integrity of the PVS during the FT anomaly scan can be achieved. The audit of the ultrasound examination of the PVS may be performed macroscopically in the second trimester of pregnancy and microscopically in the FT, with very few resources and good results. The incidence of UPSVS in a tertiary unit is higher than previously reported but the early detection is feasible, which is important for proper management and prenatal counseling. To understand the abnormalities of the hepatic fetal venous system, it is important to understand its normal embryologic development.

Acknowledgments

Microscopic images have been acquired in the Research Center for Microscopic Morphology and Immunology, University of Medicine and Pharmacy of Craiova, Romania (Manager: Laurenţiu Mogoantă).

Conflict of interest

The authors declare no conflict of interest.