For many decades, anatomists, histologists, hepatologists, and vascular biologists have been fascinated by the liver: it contains no less than five “fluidics” systems, that is, branched tubular systems that allow specific fluids to enter or leave. The liver is irrigated by two vascular systems: the portal venous system and the hepatic arterial system. Blood leaves the liver by means of the central veins that converge into the vena cava inferior. Millions of tiny sinusoidal capillaries (the sinusoids) are interposed between the afferent and efferent blood vessels. Each sinusoid is a microecological system that communicates with the rest of the body and where daily, thousands of uptake and secretion processes, biochemical conversions, immune responses, cell–cell and cell–matrix contacts, receptor-mediated signaling reactions, cell contraction or relaxation, cell motility and migration, and so on take place. Next to the above-mentioned blood vessels, the liver contains two more branched tubular systems to evacuate fluid: the lymphatics and the bile ducts. The lymphatics drain excess extracellular fluid that accumulates mainly in the space of Disse, thereby maintaining fluid homeostasis. The bile ducts evacuate an alkaline fluid than contains bile salts, bile pigments, cholesterol, lecithin and bicarbonate. Primary bile, which is produced by mature hepatocytes only, is a solution heavily modified by cholangiocytes upon its passage through the biliary tree. In view of the wealth of new studies that have been published in the past three decades, we have compiled in this special issue of “The Anatomical Record” the current concepts pertaining to supply to or drainage of fluids from the liver.

The first eight articles describe in detail the anatomy and microanatomy of the fluidics systems in embryonic and adult liver. The next five papers deal with alterations in these systems under pathological conditions: steatosis, portal hypertension, sepsis, and hepatocellular carcinoma. The last paper tackles an important question: how to preserve a donor liver before transplantation?

The vasculature of the adult liver is the result of numerous developmental processes that are often followed by extensive remodeling. Collardon-Frachon and Scoazec describe in the first article of this volume how the different vascular systems of the liver come about. The oldest vessels of the liver are the sinusoids. Next, the portal veins and efferent venous vessels form. The hepatic arteries, finally, are the last vessels to appear. Each of these vessels undergoes numerous changes before it acquires its definitive morphological and functional features. From a functional point of view, the embryonic liver may need different “fluidics” than its adult counterpart in that the primary function of the embryonic liver is hematopoiesis. Only postnatally does the role of the liver change into a vital metabolic organ requiring modulation of its blood supply and a fully developed biliary system.

The article by Collardon-Frachon and Scoazec should be read together with the paper by Roskams and Desmet. These authors describe how in the early embryo, the ductal plate forms to give rise to the intrahepatic bile ducts. The formation of these ducts is intimately linked to the development of the intrahepatic branches of the hepatic artery. The embryology of the liver remains a fascinating research field: numerous aspects await further experimental investigation.

Fasel and colleagues have studied the first and second order bifurcations of the vena porta based on vascular casts, radiology and surgical observations. They propose the “1-2-20 concept”: the portal vein bifurcates into a right and left branch (first order vessels) that subdivide further into 9 to 44 (average value: 20) second order branches. There is considerable interindividual variation in the number of second order branches. Each of these irrigates one territory; hence the human liver contains on average 20 territories. The authors compare their concept of territorialization with the classic concept of segmentation proposed by the French surgeon Claude Couinaud in 1957. New surgical techniques will undoubtedly benefit from improved anatomical knowledge of its portal irrigation.

O. and Y. Ohtani have examined lymph circulation in the liver. The hepatic lymphatic system can be subdivided into three parts depending on the location of the vessels: portal, sublobular and superficial (subcapsular). Twenty-five to 50% of the lymph that flows into the thoracic duct is produced by the liver. Most of the hepatic lymph fluid is produced by means of filtration of blood by the fenestrated endothelium lining the sinusoids. Dendritic cells, Kupffer cells and lymphocytes can extravasate into the space of Disse, located between the sinusoidal endothelium and the cords of hepatocytes, and leave the liver by means of the lymphatic circulation. Fluid originating from the space of Disse flows through channels (gaps) in the limiting plates of hepatocytes into the interstitial space of Mall, the space between the limiting plates and the portal canals. From there, the lymph reaches the prelymphatic (open) vessels that connect with downstream portal or sublobular lymphatic (closed) vessels. Close to the surface of the liver, superficial spaces of Disse drain directly into the interstitial space under the capsule of Glisson, into prelymphatic and lymphatic vessels. This fascinating aspect of liver physiology awaits further study.

Strazzabosco and Fabris summarize the functional anatomy of normal bile ducts. In the last 15 years, cholangiocytes have become a topic of intensive research. The phenotype of cholangiocytes depends on their anatomical location in the biliary tree: canals of Hering, terminal bile ductules, interlobular ducts, septal ducts, area ducts, and segmental ducts or hepatic ducts. The morphology, biochemical characteristics and functions of cholangiocytes that line this series of ducts of increasing caliber vary strongly. Next to funneling bile into the gallbladder and intestine, the cells are actively involved in bile production by means of absorptive and secretory functions. Recently, the plasticity, reactivity and stem/progenitor cell potential of cholangiocytes have become hot topics.

McCuskey reviews the unique hepatic microvasculature that comprises all intrahepatic vessels that have an internal diameter of less than 300 μm (i.e., portal venules, hepatic arterioles, sinusoids, central venules, and lymphatics). Most exchange processes take place in the sinusoids that harbor a specialized fenestrated endothelium. Since the original publication by Kiernan in 1883, several alternative organizational units for liver tissue (portal lobule, primary lobule, acinus) have been proposed. Today, 125 years later, the discussion is still ongoing. However, the classic lobule proposed by Kiernan, still fits in with most of the experimental data. Le Couteur and colleagues describe the ageing of the sinusoid, called age-related pseudo-capillarization. Clearly, sinusoidal endothelial cells are the subject of change. This may lead to reduced endocytosis of toxic compounds, such as glycated proteins, and to impaired transfer of lipoproteins from the sinusoidal lumen to hepatocytes with concomitant dislipidemia and altered interactions with the immune system. It is plausible that increased glycation products and dislipidemia lead to various manifestations of the metabolic syndrome including atherosclerosis.

Farrell and colleagues discuss the impairment of hepatic microcirculation due to fatty liver. Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming an important cause of hepatic steatosis. Among the other causes are alcohol abuse, hepatitis C infection, total parenteral nutrition, drugs or environmental hepatotoxins, profound weight loss, genetic disorders of the liver, and secondary insulin resistance. Lipid accumulation in hepatocytes and collagen deposition in the space of Disse cause narrowing of the sinusoids, which leads to reduced sinusoidal perfusion, trapping of leukocytes, activation of macrophages and increased oxidative stress. These events are profibrogenic and will exacerbate NAFLD.

Reynaert and colleagues emphasize the role of stellate cells in portal hypertension. Stellate cells are located around the sinusoidal endothelium. They possess the necessary contractile machinery to contract or dilate in response to numerous vasoactive substances. Chronic imbalance between contractile versus dilatory substances produced by the diseased liver, will lead to prolonged sinusoidal vascular resistance and subsequent portal hypertension. Colle and colleagues discuss the hemodynamic changes in splanchnic blood vessels due to portal hypertension. This pathological condition is characterized by a hyperdynamic state, high cardiac output, increased total blood volume and decreased splanchnic vascular resistance. To decompress portal circulation, portosystemic collaterals will develop. Better insight into these pathophysiological mechanisms will lead to novel therapeutic modalities in the treatment of this dreadful complication of chronic liver disease.

Severe sepsis, septic shock, and multiorgan failure are among the most common causes of morbidity and mortality in intensive care units. Spapen discusses the pathogenesis and treatment options of this life-threatening condition. Fluid-resuscitated clinical sepsis is characterized by ongoing liver ischemia, despite enhanced perfusion. Microvascular blood flow disturbances, invasion of liver tissue by neutrophils and formation of microthrombi are brought about by pathological alterations in sinusoidal endothelial cells, Kupffer cells, and adhering leukocytes. Indirect evidence supports the concept that improving hepatic microcirculation may ameliorate sepsis-induced organ failure.

Hepatocellular carcinoma is one of the five most common malignancies worldwide. These tumors are highly vascularized. The blood supply is mainly arterial. The tumor develops sinusoids lined with CD31/CD34 positive endothelial cells. Yang and Poon report that vascular endothelial growth factor (VEGF) is a potent angiogenic factor that promotes blood vessel formation in the carcinomas. Blockade of VEGF mediated angiogenesis by anti-VEGF neutralizing antibodies or by tyrosine kinase inhibitors opens promising new possibilities to treat this form of cancer.

Donor organs for liver transplantation are in short supply and have limited preservation time. As such, techniques to improve preservation of a liver under better ex vivo conditions would be of the utmost importance. In the last paper of this volume, Vekemans and colleagues describe hypothermic or normothermic machine perfusion as an alternative to simple cold storage. Many aspects of machine perfusion still need to be investigated. Evaluation in large animal models is warranted.

Much work is still to be done to advance our basic knowledge of the hepatic vasculature and of the biliary tree. However, the progress made so far in understanding the anatomy, microanatomy, cell biology and physiology of vessels and bile ducts, have given rise to new opportunities for developing new pharmacological modalities and surgical techniques in the treatment of chronic liver diseases and their often dreadful complications.

Prof. Dr. Albert Geerts Guest Editor*, Dr. Jean-Pierre Timmermans Associate Editor*, Prof. Hendrik Reynaert*, * Department of Cell Biology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Belgium.