Liver Lymphatic Imaging and Interventions: Resurrection of the Forgotten Knowledge

Abstract

Lymphatic imaging and interventions are gaining wider acceptance as the treatment of various lymphatic diseases. Meanwhile, the liver lymphatic system remains relatively unknown despite its physiological importance. Liver lymph has been at the center of the lymphatic research since the 19th century; however, the acquired knowledge has not been used in clinical research and treatment due to the lack of robust imaging methods. Recently introduced liver lymphangiography and interstitial embolization allow for the diagnosis and treatment of several diseases associated with the lymphatic system of the congested liver, providing additional treatment options for conditions that were considered incurable until now.

The lymphatic system of the body consists of multiple subsystems, each with a distinct mechanism of lymphatic production, physiological function, and fluid composition. The liver is arguably the most important lymphatic organ that contributes up to 40 to 50% flow in the thoracic duct (TD) flow in normal conditions. ¹

The liver lymphatic system has been at the center of lymphatic research since the end of the 19th century, when Ernest Starling and his predecessors performed a series of experiments measuring flow rate and content of the TD, while occluding different parts of hepatic circulation. ² An exponential increase of the liver lymph production and its high protein concentration in the congested liver were the two most crucial findings that defined the rest of the liver lymphatic research for the next 100 years.

These discoveries inspired further research on the contribution of the liver lymph to a variety of the pathological processes, such as ascites in liver cirrhosis and congestive heart failure. ^{3 4} Despite the significant progress in preclinical research, most of these ideas were not implemented in the clinical settings due to the lack of robust support by clinical lymphatic imaging and intervention techniques. However, the latest breakthroughs in lymphatic imaging and interventions have enabled us to understand the pathophysiology of some of the liver lymphatic disorders and develop the treatment approaches. ⁵

The goal of this article is to review the anatomy of the liver lymphatic system, the physiology of the production of liver lymph, the effect of contribution of changes in the liver lymph flow to various pathological conditions, and the state-of-the-art techniques in the field of liver lymphatic imaging and intervention.

Liver Lymphatic Anatomy

Liver lymph originates at the level of sinusoid space of Disse, which is a space between the sinusoid endothelium and hepatocytes. The lymphatics at the periportal space of Mall collect this initial fluid ( Fig. 1 ). The liver lymphatic vessels are divided into two distinct groups: superficial and deep ( Fig. 2 ). ⁶ Deep lymphatic vessels carrying approximately 80% of the liver lymph run alongside portal and hepatic veins and communicate with the mesenteric lymphatics and cisterna chyli. Meanwhile, superficial lymphatic vessels extending through the hepatic ligaments drain lymph from the subcapsular areas of the liver into the mediastinum, where some of them directly join TD.

Fig. 1.

Schematic drawing of the mechanism of liver lymphatic production.

Fig. 2.

Schematic drawing of the deep liver lymphatic system.

Liver Lymph Flow Physiology

Approximately 130 years ago, Ernest Starling established that the transport of the fluid through the capillary wall into the interstitial space is governed by the balance between intravascular and interstitial oncotic and hydrostatic forces as well as the permeability of the capillary wall. ⁷

J _v  =  L _p S ([ P _c  −  P _i ] – σ [ π _p  −  π _i ]).

The flow of fluid from the capillaries to the interstitial space ( J _v ) is dependent on the conductivity of the endothelium for water ( L _p ), endothelial surface area ( S ), the hydrostatic pressure difference between the capillary vessels ( P _c ), the interstitium ( P _i ), the oncotic pressure difference between the plasma ( π _p ) and the interstitial space ( π _i ), and a reflection coefficient that indexes the permeability of the microvascular to the movement of proteins ( σ ).

Starling's experiments were performed in soft tissue (isolated dog extremity) and the basic Starling's principles were applied to most of the organs, but there were some significant differences between them. One of the essential components of this equation is the permeability of the capillary wall that is different for three types of capillaries: continuous, fenestrated, and sinusoid. Sinusoid capillaries that present in the liver are the most permeable among the three due to the presence of a large opening in the wall (180 nm vs. 6–12 nm in nonsinusoidal capillaries) and a lack of basal membrane. ⁸ This allows large molecules (the most important is albumin) and even cells to pass through the sinusoid wall into the space of Disse. That results in a high concentration of the albumin and high oncotic pressure in the liver interstitial fluid ( π _i ), and subsequently in the liver lymph. This high oncotic interstitial pressure ( π _i ) serves a critical role in liver lymphatic production, balancing the low intravascular hydrostatic pressure ( P _c ) in the sinusoid that is approximately 5 mm Hg when compared with significantly higher P _c of nonsinusoidal capillaries of soft tissues (∼35 mm Hg). ^{6 9}

This high permeability of the liver sinusoidal capillary bed has a significant physiological consequence: even a slight increase in the hepatic venous pressures by any condition causing liver congestion results in a substantial increase in the albumin-rich liver lymph flow. ^{8 10}

This mechanism is involved in several disease processes, primarily ascites in liver cirrhosis or congestive heart failure. ¹¹

Liver Lymphatic Imaging

Interventional radiologists might observe unintended opacification of the liver lymphatic vessels during any procedures that involve meticulous needling of periportal structures such as transjugular intrahepatic systemic shunt (TIPS) or biliary drainage. Moreno et al first described the opacification of the liver lymphatic vessels after intraparenchymal injection of sodium diatrizoate. ¹² Until recently, the only clinical application of liver lymphangiography was to attempt to visualize and treat the metastasis from hepatocellular carcinoma (HCC). ^{13 14 15 16} This technique simply relied on the deposition of contrast material into liver parenchyma. ¹⁶ Guez et al reported a new approach of imaging of the liver lymphatics by positioning a small 21- to 25-G spinal needle under ultrasound guidance in the periportal space, which is known in the radiology literature as “periportal thickening” ( Fig. 3 ). ¹⁷ The needle is then attached to the small connecting tubes and a 3-mL syringe. Later, the appropriate position of the needle can be confirmed by observing the injected water-soluble contrast under fluoroscopy guidance to opacify liver lymphatic vessels ( Fig. 4 ). However, the opacification of lymphatic vessels fades away soon as it descended downstream only after few centimeters because of the dilution of water-soluble contrast. For this reason, in some applications, it might be better to use an oil-based contrast agent (Lipiodol) to achieve better opacification.

Fig. 3.

Ultrasound image of the 25-G needle (arrowhead) positioned in close proximity to the portal vein (arrow).

Fig. 4.

Fluoroscopic image of the liver lymphangiography performed through 25-G needle (arrow). It demonstrates filling of the dilated liver lymphatic duct with abnormal hepatoduodenal connections (arrowhead) and leak of the contrast in duodenum.

Although it seems very difficult to puncture such a tiny structure, according to our experience, liver lymphangiography could be performed in the majority of cases. The tendency of congested liver having dilated periportal lymphatics might be a plausible explanation for this.

Liver lymphatic vessels can sometimes be dilated large enough even to be directly catheterized using a 0.0010-inch wire and a microcatheter. Although this might not be feasible in every case, once achieved, direct catheterization of liver lymphatics can provide better imaging and more stable delivery of the embolization material than simple needling ( Fig. 5 ).

Fig. 5.

Fluoroscopic image of the liver lymphangiography, performed through the microcatheter (arrows).

The relatively small size of the lymphatic vessels, however, makes their visualization under fluoroscopy difficult due to poor contrast resolution of this modality. Most modern angiography units, however, can perform rotational computed tomography (CT). A combination of the fluoroscopy-guided injection and rotation CT can provide much better imaging of the liver and retroperitoneal lymphatics ( Fig. 6 ).

Fig. 6.

Rotational CT of the liver lymphangiography (arrowhead) demonstrates leakage of the contrast in the duodenum in a patient with protein losing enteropathy (arrowhead).

Nevertheless, the main challenge of the imaging of the liver lymphatic system is its complex and variable anatomy consisting of multiple interconnected lymphatic networks. Opacification of one of these networks does not necessarily provide the diagnostic value of the condition, if the abnormal lymphatic resides in the different territory. Development of the new lymphatic imaging agents that are “excreted” by the liver lymphatic system, similar to now abandoned intravenous cholangiogram, can potentially provide much better information about liver lymphatic disorders.

Importance of the Liver Lymphatics to Various Disease Processes

As mentioned earlier, Ernest Starling's observation of manifold increase of the liver lymphatic flow in patients with liver congestion provided fertile ground for further investigation of the effect of this physiological process in different conditions. A significant amount of the research was dedicated to the contribution of the liver lymphatic system to the pathophysiology of liver ascites in both congestive heart failure and liver cirrhosis. The concept was that the increase of liver lymphatic flow could not be drained in its entirety and “spills” over into the abdominal cavity. ¹⁸ The researchers described it as “weeping of the lymph from the surface of the liver” after occluding hepatic veins of dogs, resulting in developing the ascites. ⁹ The ascites in these experiments and Budd-Chiari syndrome have been characterized by a high concentration of albumin in the ascitic fluid, reflecting a high concentration of albumin in the liver lymph. In contrast, a low concentration of albumin is a feature of ascites in advanced liver cirrhosis, which reflects the different origins, which were considered to be extrahepatic portal bed of mesentery over the years. ¹⁹

Liver lymphorrhea is a condition in which there is a leakage of the liver lymph into the peritoneal cavity, typically after abdominal surgery, which causes the disruption of the liver lymphatic ducts. ^{20 21} Over the years, it has been a relatively underrecognized condition due to the absence of specific liver lymphatic imaging. Application of liver lymphangiography allows recognition of identification of the leak and embolization treatment ( Fig. 7 ). ¹⁷

Fig. 7.

Fluoroscopic image of the liver lymphangiography performed through 25-G needle (arrowhead) demonstrating leak in the peritoneum (arrow) in patient with ascites post–Kasai procedure.

Protein-losing enteropathy (PLE) is a condition where the proteins are lost in the intestinal tract. It was reported to be associated with over 60 diseases, which can be divided into two main groups: gastrointestinal disease and lymphatic congestion that are often cardiac in origin. ²² Until recently, the pathophysiology of the latter had been poorly understood. The latest application of liver lymphangiography to patients with PLE and congenital heart disease demonstrated abnormal hepatoduodenal communications between liver lymphatics and the duodenum ( Fig. 4 ). ²³ These unusual hepatoduodenal communications represent an anatomical variant of the upper retroperitoneal lymphatic network, in which some of the lymphatic vessels approach close to the duodenal submucosa. The increased flow of albumin-rich liver lymph from the congested liver overdistended these abnormal lymphatic vessels, resulting in lymph leakage into duodenum lumen.

Chylous ascites is one of the most challenging conditions to treat primarily because of the difficulty of imaging the intestinal lymphatic system. Chylous lymphatic is a fluid solely formed in the small bowel and travels through the mesenteric lymphatic system to join the cisterna chyli via its intestinal trunk. Because the standard route of contrast medium injection is through soft tissue of lower extremity or inguinal lymph nodes, it usually does not move against the flow direction of the chylous lymphatic fluid. Thus, the intestinal trunk and its upstream mesenteric lymphatic system are rarely visualized in any lymphatic examination. Mesenteric lymph node lymphangiography offers opacification of the upstream mesenteric chylous lymphatic system and can detect lymphatic leakage from the intestinal trunk or the more proximal parts of the mesenteric lymphatic system ( Fig. 8 ). The disadvantage of mesenteric lymphangiography is that it requires exploratory laparotomy to expose the mesenteric lymph nodes for the ultrasound-guided puncture. ²⁴ Because the liver lymphatics communicate with the intestinal lymphatics through multiple channels, liver lymphangiography can elucidate the source of chylous ascites sometimes, if not always. It has advantages over the mesenteric lymphangiography in these conditions because it does not require surgical procedure.

Fig. 8.

Fluoroscopic image of the intraoperative mesenteric lymphangiography performed by direct injection of the mesenteric lymph node (arrow).

Liver Lymph and Thoracic Disorders

As mentioned earlier, the liver lymphatics communicate with the chest cavity through falciform and coronal ligaments. In our practice, we observe communication between the liver lymphatics and the thoracic cavity through hepatic ligaments causing plastic bronchitis and chylothorax ( Fig. 9 ). It is possible that prevalence of these communications is much more common and can explain some pulmonary lymphatic conditions.

Fig. 9.

Fluoroscopic image of the liver lymphangiography performed through microcatheter position in the liver lymphatics, showing the lymphatic duct extending into mediastinum (arrow) in a patient with congenital heart disease and plastic bronchitis.

Liver Lymphatic Interventions

The small size of the lymphatic vessels makes interventions very challenging. Recently, however, it became feasible thanks to the technique of interstitial embolization. ²⁵

Interstitial embolization is performed using N-butyl cyanoacrylate (NBCA) glue diluted with lipiodol at a ratio between 1:2 and 1:3 and is injected through the needle positioned in the lymphatic vessel–rich region. Prior to injection, the needle and lymphatic vessels are flushed with Dextrose 5% solution to allow for further propagation of the glue into the distant part of the hepatic lymphatic vessels from the injection site. This technique was initially described for the treatment of postsurgical liver lymphatic lymphorrhea, where we found it very effective ( Fig. 7 ). ¹⁷

PLE is a devastating complication of patients with congenital heart disease. As mentioned earlier, liver lymphangiography demonstrated that the cause of this condition is abnormal hepatoduodenal communications that allow albumin-rich lymph to leak into the duodenum. The application of the liver lymphangiography, followed by interstitial embolization of these abnormal connections, was suggested as a potential treatment method of PLE in this patient group. ^{23 26} The goal of embolization here is to deliver NBCA glue to the leaking point in the duodenum, all the way through from liver lymphatics to the periduodenal retroperitoneal lymphatics that finally distribute in the duodenal mucosa. Injection of the methylene blue through the liver lymphangiography route and simultaneous endoscopic monitoring of duodenal mucosa helps confirm that liver lymph leakage into the duodenum is the cause of PLE. Itkin et al described sustained improvement of the serum albumin level in three patients, in whom the embolic material reached close to the duodenal wall. ²³ Maleux et al also reported the successful treatment of seven PLE patients in the same manner. Among them, six patients showed significant improvement in the serum albumin level and quality of life with minimal procedure-related complications. ²⁶

Conclusion

The role of the liver lymphatic system in the condition of liver congestion was established decades ago. However, this knowledge has been forgotten for generations due to the inability to visualize liver lymphatics. The liver lymphangiography and interstitial embolization provide us the opportunity to discover and even treat the abnormal liver lymphatic connection resulting in clinical presentation. Newer lymphatic imaging techniques and lymphatic imaging agents need to be developed to explore this field further.