Quantitative assessment of the rat intrahepatic biliary system by three-dimensional reconstruction

The anatomical details of the biliary tree architecture of normal rats and rats in whom selective proliferation was induced by feeding alpha-naphthylisothiocyanate (ANIT) were reconstructed in three dimension using a microscopic-computed tomography scanner. The intrahepatic biliary tree was filled with a silicone polymer through the common bile duct and each liver lobe embedded in Bioplastic; specimens were then scanned by a microscopic-computed tomography scanner and modified Feldkamp cone beam backprojection algorithm applied to generate three-dimensional images. Quantitative analysis of bile duct geometry was performed using a customized software program. The diameter of the bile duct segments of normal and ANIT-fed rats progressively decreased with increasing length of the biliary tree. Diameter of bile ducts from ANIT-fed rats (range, 21 to 264 microm) was similar to that of normal rats (22 to 279 microm). In contrast, the number of bile duct segments along the major branch reproducibly doubled, the length of the bile duct segments decreased twofold, and the length of the biliary tree remained unchanged after ANIT feeding. Moreover, the total volume of the biliary tree of ANIT-fed rats was significantly greater (855 microl) than in normal rats (47 microl). Compared with normal rats, the total surface area of the biliary tree increased 26 times after ANIT-induced bile duct proliferation. Taken together, these observations quantitate the anatomical remodeling after selective cholangiocyte proliferation and strongly suggest that the proliferative process involves sprouting of new side branches. Our results may be relevant to the mechanisms by which ducts proliferate in response to hepatic injury and to the hypercholeresis that occurs after experimentally induced bile duct proliferation.     

Arterial supply and biliary drainage of the dorsal liver: A dissection study using controlled specimens

Liver surgeons favor using the entity called the 'dorsal liver' (i.e. the caudate lobe and other paracavally located liver parenchyme of segments 7 and 8). According to minute dissection of 48 livers, we describe the territories of the left/right portal veins, hepatic ducts and hepatic arteries in the dorsal liver. In the caudate lobe, the right hepatic artery, rather than the left hepatic artery (23/48 vs 19/48 for right vs left, respectively), tended to supply the 'left' portal vein territory. Similarly, paradoxical drainage patterns, such as the right hepatic duct draining the left portal vein territory, were found in seven of 48 livers. In the territory of the hilar bifurcation, right hepatic artery dominance was also evident and various bile drainage patterns were found. These included double drainage by the bilateral hepatic ducts (3/48) and drainage into the confluence of bilateral ducts (6/48). In contrast, the arterial supply and biliary drainage of the paracavally located parenchyme of segments 7 and 8 usually depended on the proper segmental arteries and ducts and their variations were within the range of those found in other parts of the right lobe. Therefore, the dorsal liver concept may not be anatomical but, rather, simply aimed at usefulness in surgery. Nevertheless, clear subdivision of the caudate lobe according to biliary drainage and/or arterial supply seemed difficult because of the paradoxical relatioships among the portal vein, hepatic artery and bile duct. Consequently, the present results support extended surgery based on the dorsal liver concept for carcinomas involving the caudate lobe.     

Three liver grafts from a deceased whole liver

Although the lateral segment (LS) from the split-liver of a deceased donor or a live donor can increase the organ pool of pediatric patients awaiting liver transplantation, the shortage of organ donation in Asia countries is still serious and results in high death rates of pediatric patients. The medial segment (MS) of the liver is sacrificed during the standard technique of splitting a whole liver into an LS and an extended right liver because the cutting sites of portal vein, hepatic artery and bile duct are all in the bifurcation of the liver hilum to have adequate length of vascular and biliary pedicles for easier grafting. However, the surgical techniques of vascular and biliary reconstructions for liver transplantation, particularly from the experiences of living donor liver transplantation, have been much improved in the last decade. Therefore it may be possible for an additional MS of the liver to be an isolated graft for a small recipient on the premise that grafts of right lobe (RL) and LS are minimally injured. In light of detailed reviews of anatomies of hepatic arteries, hepatic veins, portal veins and bile ducts, the dissection and reconstruction of vessels and bile ducts for the MS can possibly be performed if the extra-hepatic length of the artery to the MS is long enough. As the artery for the MS, middle hepatic artery (MHA), usually derives from a branch of the left hepatic artery and often in the liver parenchyma, the length is usually too short to be reconstructed. If the MHA for the MS is isolated and its extra-hepatic length is more than 1cm, triple liver grafts from a deceased whole liver, consisting of the RL, MS and LS may be possible. The anatomies of the hepatic artery in abdominal computed tomography (CT) or magnetic resonance imaging (MRI) for live liver donors in our institution were retrospectively analyzed. The results showed that three types of hepatic arterial anatomies could be considered for possible recovery of triple segments: type I is an accessory left gastric artery to feed the lateral segment; type II is an isolated MHA; type III is an early bifurcation of the left hepatic artery and MHA.     

Embryology of Extra‐ and Intrahepatic Bile Ducts,the Ductal plate

In the human embryo, the first anlage of the bile ducts and the liver is the hepatic diverticulum or liver bud. For up to 8 weeks of gestation, the extrahepatic biliary tree develops through lengthening of the caudal part of the hepatic diverticulum. This structure is patent from the beginning and remains patent and in continuity with the developing liver at all stages. The hepatic duct (ductus hepaticus) develops from the cranial part (pars hepatica) of the hepatic diverticulum. The distal portions of the right and left hepatic ducts develop from the extrahepatic ducts and are clearly defined tubular structures by 12 weeks of gestation. The proximal portions of the main hilar ducts derive from the first intrahepatic ductal plates. The extrahepatic bile ducts and the developing intrahepatic biliary tree maintain luminal continuity from the very start of organogenesis throughout further development, contradicting a previous study in the mouse suggesting that the extrahepatic bile duct system develops independently from the intrahepatic biliary tree and that the systems are initially discontinuous but join up later. The normal development of intrahepatic bile ducts requires finely timed and precisely tuned epithelial–mesenchymal interactions, which proceed from the hilum of the liver toward its periphery along the branches of the developing portal vein. Lack of remodeling of the ductal plate results in the persistence of an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration. This abnormality has been termed the ductal plate malformation. Anat Rec, 291:628–635, 2008. © 2008 Wiley‐Liss, Inc.     

左外叶活体肝移植的解剖学研究

目的：模拟左外叶活体肝移植门静脉、肝动脉和胆管的切取方法。方法：解剖正常人肝脏标本30具，观察肝脏铸型标本30具，测量门静脉、肝动脉及胆管长度、管径及属支或分支分布情况。结果：左外叶门静脉的血供来自门静脉左支，主要为左外叶上段门静脉支、左外叶下段门静脉支；动脉主要来源于肝固有动脉、肝左动脉、肝中动脉，偶有迷走动脉支；胆道引流属支有左外叶上段胆管支、左外叶下段胆管支。结论：左外叶解剖变异较多，活体取肝前应仔细研究其结构特点，设计合理的切取模式；对门静脉、肝动脉和胆管支需行必要的整形，以便与受体相应的管道进行吻合。     

Phylogenetic analyses of the hepatic architecture in vertebrates

The mammalian liver has a structural and functional unit called the liver lobule, in the periphery of which the portal triad consisting of the portal vein, bile duct and hepatic artery is developed. This type of hepatic architecture is detectable in many other vertebrates, including amphibians and birds, whereas intrahepatic bile ducts run independently of portal vein distribution in actinopterygians such as the salmon and tilapia. It remains to be clarified how the hepatic architectures are phylogenetically developed among vertebrates. The present study morphologically and immunohistochemically analyzed the hepatic structures of various vertebrates, including as many classes and subclasses as possible, with reference to intrahepatic bile duct distribution. The livers of vertebrates belonging to the Agnatha, Chondrichthyes, Amphibia, Aves, Mammalia, and Actinopterygii before Elopomorpha, had the portal triad‐type architecture. The Anguilliformes livers developed both periportal bile ducts and non‐periportal bile ducts. The Otocephala and Euteleostei livers had independent configuration of bile ducts and portal veins. Pancreatic tissues penetrated the liver parenchyma along portal veins in the Euteleostei. The liver of the lungfish, which shares the same origin with amphibians, did not have the portal triad‐type architecture. Teleostei and lungfish livers had ductular development in the liver parenchyma similar to oval cell proliferation in injured mammalian livers. Euteleostei livers had penetration of significant numbers of independent portal veins from their intestines, suggesting that each liver lobe might receive a different blood supply. The hepatic architectures of the portal triad‐type changed to non‐portal triad‐type architecture along the evolution of the Actinopterygii. The hepatic architecture of the lungfish resembles that of the Actinopterygii after Elopomorpha in intrahepatic biliary configuration, which may be an example of convergent evolution.     

Quantification of the intrahepatic biliary tree during human fetal development

Development and differentiation of bile ducts have been studied for the understanding of pathogenesis of biliary atresia and other diseases of the intrahepatic biliary tree. The aim of this study is to correlate the type of biliary structure with the size of the portal tract and the gestational age. Twenty-four human livers were studied. Fetuses were assigned to four gestational age groups: group I, up to 20 postfecundation weeks (PFW); group II, from 21–26 PFW; group III, from 27–32 PFW; and group IV, from 33–38 PFW. In each specimen, 30 portal tracts were classified as small, medium, or large according to the diameter of the portal vein. In order to identify the bile duct cells, the sections were immunolabeled with anti-cytokeratin antibody, and the biliary structure was classified as absent (bile ducts (BD) = 0), presence of bile duct cells without lumen (BD = 1), or presence of bile duct with lumen (BD = 2). In the small portal tracts, either there were no biliary structures or just a few. There was a substantial increase in the number of medium portal tracts that included a bile duct as a function of gestational age. The majority of large portal tracts exhibited a bile duct. In human fetus up to 20 PFW, it is possible to find 70% of portal tracts without bile ducts, and at 38 PFW it is expected that more than 50% of the portal tract has a BD > 0. We suggest the use of the diameter of the portal vein and the gestational age for the quantification of biliary structures and the evaluation of maturity of intrahepatic biliary tree. Anat. Rec. 251:297–302, 1998. © 1998 Wiley-Liss, Inc.     

Connection of ductlike structures induced by a chemical hepatocarcinogen to portal bile ducts in the rat liver detected by injection of bile ducts with a pigmented barium gelatin medium.

Newly found metaplastic ductlike structures that form in the liver of rats exposed to carcinogens are connected to preexisting bile ducts. Male Fischer rats fed a diet of N-2-acetylaminofluorene in a choline-deficient diet (CDAAF) develop a massive proliferation of oval cells which appear to differentiate into bile-ductlike structures. However, unlike normal or proliferating bile ducts, these ductlike structures contain alpha-fetoprotein (AFP) and albumin, which are markers for proliferating hepatocytes and some hepatocellular carcinomas. Bile duct injections with a green pigmented barium gelatin medium filled the lumens of the ductlike structures and typical ductlike structures induced by the CDAAF diet, as well as the proliferating bile ducts induced by the noncarcinogenic alpha-naphthylisothiocyanate (ANIT), and the ducts in the normal controls. AFP was present in the ductlike structures in the rats fed AAF, but not in the bile ducts of animals fed ANIT. These studies suggest that most, if not all, of the ductlike structures produced during chemical hepatocarcinogenesis are derived from bile ducts, yet have the capacity to produce AFP and albumin.     

Angioarchitecture of the rabbit extrahepatic bile ducts and gallbladder

The angioarchitecture of extrahepatic bile ducts and gallbladder of the miniature rabbit was studied by scanning electron microscopy (SEM) of vascular corrosion casts. Light microscopy of Masson-stained, paraffin-embedded transverse tissue sections served to attribute cast vascular structures to defined layers of bile ducts and gallbladder. In all segments of the bile tract, a mucosal and a subserosal vascular network was found. In glandular segments, the mucosal network was composed of a meshwork of subepithelial and circumglandular capillaries, which serve the mucosal functions. Differences in the angioarchitectonic patterns existed only in the subserosal networks as hepatic ducts own one supplying arteriole only, while the common bile duct owns a well-defined rete arteriosum subserosum. A well-developed dense subserosus venous plexus was present throughout the bile tract. Vascular patterns of the gallbladder body resembled those of the bile duct, whereby the dense subserous venous plexus was located close to the mucosal capillary network. The subserosal network in the neck of the gallbladder resembled that of the cystic duct. Spatial changes of the mucosal vascular network during volume changes of the gallbladder were documented. Measurements from tissue sections revealed bile tract diameters of 220-400 microm (extrahepatic ducts), 500-650 microm (cystic duct), and 4-6 mm (common bile duct). Data gained from high-powered SEM micrographs of vascular corrosion casts revealed vessel diameters of 200 microm (cystic artery), 90-110 microm (cystic vein), 30-40 microm (feeding arterioles), and 25-110 microm (subserosal venules). Crypt diameters in the filled gallbladder were 300-1,500 mum; those in the contracted organ were 100-600 microm.     

Destruction of canals of Hering in primary biliary cirrhosis

The canals of Hering (CoH), converging from the hepatic lobule onto the portal tract, connect bile canaliculi to the interlobular bile ducts, and represent the most proximal portion of the bile drainage pathway with a cholangiocyte lining. In this study we sought to ascertain whether this proximal pathway is involved by the disease process in primary biliary cirrhosis (PBC), which uniformly affects small bile ducts while sparing medium- and large-sized ducts. Ten biopsy specimens with early-stage PBC were compared with 6 normal control livers. Adjacent 4-micron-thick sections of routinely processed, formalin-fixed tissue were immunostained for CK19 and HLA-DR. Each terminal portal tract was assigned a stage: 0, normal; 1, bile duct damage or loss; 2, bile ductular proliferation; or 3, periportal fibrosis. The ratio of the number of CoH to number of portal tracts (i.e., the c/p ratio) was calculated for the control biopsies and individual portal tracts at each stage of PBC. The numbers of CoH were decreased in all stages of PBC (P <0.0001), with the fewest found around portal tracts at stages 0 and 1 and the most around portal tracts at stages 2 and 3, but never at normal levels. HLA-DR was expressed focally on bile ducts and CoH in PBC, but was absent in normal controls. We conclude that CoH are destroyed in PBC in concert with the destruction of small bile ducts. This destruction appears to be an early event, because CoH numbers are lowest around stage 0 portal tracts, which still contain normal bile ducts.     

Aberrant bile ducts, 'remnant surface bile ducts,' and peribiliary glands: descriptive anatomy, historical nomenclature, and surgical implications

The term "aberrant bile ducts" has been used to designate three heterogeneous groups of biliary structures: (1) bile ducts degenerating or disappearing (unknown etiology, diverse locations); (2) curious biliary structures in the transverse fissure; and (3) aberrant right bile ducts draining directly into the common hepatic duct. We report our observations on these three groups. Twenty-nine fresh human livers of stillborns and adults were injected differentially with colored latex and dissected. Adult livers showed portal venous and hepatic arterial branches, and bile ducts not associated with parenchyma, subjacent to and firmly adherent with the liver capsule: elements of ramifications of normal sheaths were present on the liver's surface. These ramifications, having lost parenchyma associated with them, then sequentially lost their portal branches, bile ducts and arterial branches. This process affected the ramifications of the sheaths in the left triangular ligament, adjacent to the inferior vena cava, in the gallbladder bed and anywhere else on the liver's surface and resulted in the presence of bile ducts accompanied by portal venous and/or hepatic arterial branches and not associated with parenchyma for a period of time. This first group represented normal bile ducts that do not meet the criteria of aberration and could be appropriately designated "remnant surface bile ducts." Such changes were not found in the transverse fissures and review of the literature revealed that the curious biliary structures are the microscopic peribiliary glands. The third group met the criteria of aberration and the anatomy of a representative duct is described.     

Distortion in TGFβ1 peptide immunolocalization in biliary atresia: Comparison with the normal pattern in the developing human intrahepatic bile duct system

Biliary atresia is an important cause of neonatal obstructive jaundice in which there is inflammation, sclerosis and eventual obliteration of the bile duct system. Its onset may be antenatal, affecting the normal development of the biliary system. The intrahepatic biliary system is derived from the ductal plate, a sheath of cuboidal epithelium that appears at the hepatocyte-mesenchymal junction around the portal vein branches at 6 weeks gestation. This epithelial structure is moulded into a network of tubular bile ducts by the proliferating mesenchyme. Certain portions of the ductal plate are selected to become definitive bile ducts, while redundant biliary epithelium is deleted. The molecular dynamics controlling the intra-uterine development of the biliary system in humans are not yet clearly understood. Transforming growth factor-β1 is a cytokine that stimulates mes-enchymal proliferation and inhibits epithelial growth, and has been shown to be important in organogenesis. In the present study, the pattern of TGFβ1 peptide immunolocalization was investigated with the aid of computerized image analysis, in normal human bile duct development and in biliary atresia. TGFβ1 peptide was detected within hepata-cytes and ductal plate epithelium from 7 weeks gestation; increased TGFβ1 immunoreactivity was present within the epithelium of developing bile ducts at 13 weeks gestation, and apical polarization of the cytokine was observed from 16 weeks gestation. In biliary atresia, the TGFβ1 immunoreactivity pattern within the bile duct structures at the porta hepatis and within intrahepatic portal tracts resembled that of the primitive ductal plate, and there was no significant apical polarization. This may indicate a developmental arrest in the normal ductal plate remodelling process in biliary atresia, and suggests an underlying epithelial-mesenchymal interactive disorder.     

Microradiography of the rabbit's hepatic microcirculation. The similarity of the hepatic portal and pulmonary arterial circulations

Examination of microradiographs of liver indicate that the hepatic arteries supply the richly anastomosing arterial plexus around the biliary ducts. This arterial plexus supplies the portal veins directly and the peripheral hepatic sinusoids. Arterial “boosters” penetrating deep within the lobule were not seen. Hepatic veins receive sinusoids at irregular angles and frequent intervals, whereas portal veins distribute flow through short right angle inlet venules spaced at greater intervals. Pulmonary arteries also distribute flow to capillaries through short right angle precapillaries and pulmonary veins receive capillary drainage at irregular angles and frequent intervals. The location of capillary beds of both liver and lung only 10 to 30 μ from inflow channels appears “ideally” suited for circulations of low vascular resistance. The analogy of liver and lung relates biliary system to airway, hepatic artery to bronchial artery, portal vein to pulmonary artery, hepatic vein to pulmonary vein and ductus venosus to ductus arteriosus. In particular, should the pulmonary artery be considered a “pulmonary portal vein”.     

PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury

The accumulation of myofibroblasts and fibrosis around proliferating bile ducts in cholestatic liver disease has been attributed to the proliferation and phenotypic modulation of portal fibroblasts, whereas the contribution of hepatic stellate cells remains uncertain. There is increasing evidence to indicate that bile ducts may stimulate chemoattraction of hepatic stellate cells (HSC). In the present study, we undertook dynamic tests to examine such a possibility and to investigate the role of two potential mediators: platelet-derived growth factor-BB (PDGF-BB) and endothelin-1. Cholestasis was induced by bile duct ligation in rats. HSC were isolated from normal rats and culture activated into myofibroblasts expressing PDGF-beta receptors. Migration of myofibroblastic HSC was investigated in a Transwell chemotaxis filter assay. As compared with basal conditions, PDGF-BB (100 microg/l) and endothelin-1 (10(-8) M) induced a 3-fold and 1.7-fold increase in HSC migration, respectively. Bile duct segments isolated from cholestatic rats triggered a 3-fold increase in migration. This stimulation was significantly more potent than that observed in the presence of normal bile ducts. It was inhibited by neutralizing anti-PDGF antibodies and by STI571 PDGF receptor tyrosine kinase inhibitor, by 60% and 85%, respectively, whereas Bosentan, an endothelin receptor antagonist, had no significant inhibiting effect. In bile duct segments from cholestatic rats PDGF-B chain mRNA was detected at higher levels than in controls, whereas PDGF-BB was immunolocalized in bile duct epithelial cells. The results indicate that chemotaxis of HSC towards bile duct structures may contribute to the development of periductular fibrosis in cholestatic disorders, and that PDGF-BB is the major mediator in this process. In addition, anti-liver fibrogenic properties of STI571 are suggested by potent inhibition of myofibroblastic HSC function.     

Surgical anatomy of the vasculobiliary apparatus at the hepatic hilum as applied to liver transplantations and major liver resections

Introduction

To evaluate the hepatic arterial, bile duct and portal venous anatomy as applicable to major liver resections.

Relating function to branching geometry: a micro-CT study of the hepatic artery, portal vein, and biliary tree

Utilizing micro-computed tomography images, the hierarchical structure, interbranch segment lengths and diameters of a hepatic artery, a portal vein, and two biliary trees from intact rat liver lobes were characterized. The data were investigated by analyzing the geometric properties of the vascular structures, such as how interbranch segment diameters change at bifurcation points. In the case of the hepatic artery and portal vein trees (in which the flow rate is high by comparison with that in the biliary tree), the vascular geometry is consistent with a fluid transport system which aims to simultaneously minimize both the power loss of laminar flow, and a cost function proportional to the total volume of material needed to maintain the system (lumenal contents). In comparison, the biliary tree (which has a low flow rate and an opposite flow direction to that of the hepatic artery and portal vein) was found to have a geometry in which the lumen cross-sectional area is maintained at bifurcations. These findings imply that the histological makeup and therefore the pathophysiology of biliary tree vasculature are likely very different from that of the vasculature within the systemic arterial tree. The extent to which the characteristic variability/scatter in the data may have resulted from imaging and/or measurement errors was examined by simulating such errors in a theoretical tree model and comparing the results with the measured data.     

Preferential differentiation of the bile ducts along the portal vein in the development of mouse liver

Summary The development of bile ducts in the mouse liver was studied histochemically, with special reference to their preferential differentiation around the portal vein. Both portal vein and hepatic vein shared a common origin, the omphalomesenteric vein. In the early development of the liver, haematopoietic cells were predominant around both veins. With the progressive development of intrahepatic bile ducts, the following three steps were observed: cluster formation of type I hepatocytes around the portal vein, formation of primitive bile duct structures and basal lamina, then formation of ducts surrounded by connective tissue structures composed of type I and type III collagens and lectin-binding sites, which were predominant around the portal vein compared to the hepatic vein. These results suggest that the deposition of abundant connective tissue structures around the portal vein is a prerequisite for the cell differentiation and basal lamina formation in the bile duct precursors. A possible mechanism of the aggregation of type I hepatocytes around the portein vein is also discussed.     

Portal tract fibrogenesis in the liver

The portal area is the 'main entrance' and one of the two main exits of the liver lobule. Through the main entrance portal and arterial blood reach the liver sinusoids. Through the exit the bile flows towards the duodenum. The three main structures, portal vein and artery with their own wall (and vascular smooth muscle cells) and bile duct with its basal membrane, are surrounded by loose myofibroblasts and by the first layer of hepatocytes and non-parenchymal cells. Chronic diseases of the liver can lead to development of liver cirrhosis, characterized by formation of fibrotic septa which can be portal-portal in the case of the chronic biliary damage or portal-central in the case of the chronic viral hepatitis. Central-central septa can also be observed under other pathological conditions. When damaging noxae are introduced to the liver, inflammatory cells are first recruited to the portal field, the first layer of hepatocytes may be destroyed (enlargement of the portal field) and portal (myo)fibroblasts become activated. A similar reaction may take place when the target of inflammation is the bile duct with consecutive reduction of the bile flow, activation of the portal (myo)fibroblasts, proliferation of bile ducts and destruction of the hepatocytes around the portal field. Increased matrix deposition may be the consequence. During the past years several publications dealt with the pathomechanisms of portal fibrogenesis as well as with its resolution. One of the most intriguing observations was that it is not hepatic stellate cells of the hepatic sinusoid, but portal (myo)fibroblasts which rapidly acquire the phenotype of 'activated' (myo)fibroblasts in the early stages of cholestatic fibrosis. These may also become the main mesenchymal cells of the porto-portal or porto-central fibrotic septa. This article reviews the similarities as well as differences between the mesenchymal cells of the portal tract and of the fibrotic septa vs 'activated' stellate cells of the hepatic sinusoids, and discusses the debate over their relative contributions to liver fibrogenesis.     

Distribution and possible origins of substance P-containing nerve fibers in the rat liver.

The distribution and possible origins of substance P-containing nerve fibers in the rat liver were investigated by immunohistochemistry and nerve transection. Nerve fibers with substance P-like immunoreactivity formed a more complex network than previously known in the walls of portal vein branches. Substance P-immunoreactive fibers were seen not only in and around the walls of the hepatic artery, but also in close association with the hepatic veins and bile ducts. Transection of the greater splanchnic nerves and/or the vagus nerves indicated that substance P-immunoreactive fibers in the walls of the portal and hepatic veins enter the liver via both nerves, and that those associated with the hepatic artery and bile ducts stem from the greater splanchnic nerves. The widespread distribution of hepatic substance P and its complex innervation pattern within the liver suggest that it is involved in a variety of physiological processes in this organ.