The Role of Lymphatics in Cholestasis: A Comprehensive Review

Abstract

Cholestatic liver disease affects millions of people worldwide and stems from a plethora of causes such as immune dysfunction, genetics, cancerous growths, and lifestyle choices. While not considered a classical lymphatic organ, the liver plays a vital role in the lymph system producing up to half of the body's lymph per day. The lymphatic system is critical to the health of an organism with its networks of vessels that provide drainage for lymphatic fluid and routes for surveilling immune cells. Cholestasis results in an increase of inflammatory cytokines, growth factors, and inflammatory infiltrate. Left unchecked, further disease progression will include collagen deposition which impedes both the hepatic and lymphatic ducts, eventually resulting in an increase in hepatic decompensation, increasing portal pressures, and accumulation of fluid within the abdominal cavity (ascites). Despite the documented interplay between these vital systems, little is known about the effect of liver disease on the lymph system and its biological response. This review looks at the current cholestatic literature from the perspective of the lymphatic system and summarizes what is known about the role of the lymph system in liver pathogenesis during hepatic injury and remodeling, immune-modulating events, or variations in interstitial pressures.

A soft, bioinspired artificial lymphatic system for interactive ascites transfer

“…Therefore, inspired by lymphatic valves, duckbill valves were introduced into the system to guide ascites through the ducts to the urinary bladder. Lymphatic circulation is driven by muscular movement, such as vascular pulsation and intestinal peristalsis, so periodic pressure was applied on the pump cavity as the driving force of the artificial lymphatic system 37,38 . After the pumps were subcutaneously implanted, various failures were reported, such as duct blockage and abdominal pain.…”

“…Lymphatic circulation is driven by muscular movement, such as vascular pulsation and intestinal peristalsis, so periodic pressure was applied on the pump cavity as the driving force of the artificial lymphatic system. 37,38 After the pumps were subcutaneously implanted, various failures were reported, such as duct blockage and abdominal pain. Most of the abnormities could be reflected by unexpected fluctuations in the flow rate, and thus, wireless real-time detection of the flow rate can inform the system about its own operating status.…”

Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma

“…The role of lymphangiogenesis has been investigated in different chronic hepatobiliary diseases, as well as in ischemia–reperfusion injury [ 15 , 16 , 23 , 24 , 25 , 26 , 27 ]. In fact, the activation of lymphangiogenesis has been found in chronic viral hepatitis, non-alcoholic fatty liver disease, alcohol-associated liver disease, primary biliary cholangitis, and primary sclerosing cholangitis, resulting in an increased number of lymphatic vessels near areas of fibrosis in conjunction with an inflammatory infiltrate [ 15 , 16 , 23 , 24 , 25 , 26 ].…”

“…The role of lymphangiogenesis has been investigated in different chronic hepatobiliary diseases, as well as in ischemia–reperfusion injury [ 15 , 16 , 23 , 24 , 25 , 26 , 27 ]. In fact, the activation of lymphangiogenesis has been found in chronic viral hepatitis, non-alcoholic fatty liver disease, alcohol-associated liver disease, primary biliary cholangitis, and primary sclerosing cholangitis, resulting in an increased number of lymphatic vessels near areas of fibrosis in conjunction with an inflammatory infiltrate [ 15 , 16 , 23 , 24 , 25 , 26 ]. Moreover, in non-alcoholic steatohepatitis, increased levels of oxidized low-density lipoproteins promote inflammatory signals and reduce Prox1 levels, leading to decreased lymphatic stability and alterations in liver homeostasis [ 23 ].…”