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

Authors


Abstract

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.

DEVELOPMENT OF EXTRAHEPATIC BILE DUCTS

In the human embryo, the first anlage of the bile ducts and the liver is the hepatic diverticulum or liver bud. It starts as a thickening of the endoblastic epithelium in the ventral wall of the cephalad portion of the foregut (the future duodenum), near the origin of the yolk sac; this area is termed the anterior intestinal portal. This occurs around the seven-somite (2.5-mm) stage on the eighteenth day. In the 19-somite (3-mm, 22-day) embryo the diverticulum is formed. In the 22-somite embryo, the hepatic diverticulum is a well-defined hollow structure. From the ventral and lateral surfaces of the diverticulum, on which the endoderm is in contact with the bulk of the mesoderm of the septum transversum (between the pericardial and peritoneal cavities), short sprouts of endodermal cells extend into the septum transversum to form the earliest anlage of the liver (Severn,1972).

In the embryo approximately 5 mm in length, the diverticulum also shows a protruding bud in its distal part. Some investigators accordingly distinguish in the hepatic diverticulum a cranial part (pars hepatica) and a caudal part (pars cystic; Am,1963).

The caudal bud or pars cystica grows in length and represents the anlage of the gallbladder, the cystic duct, and common bile duct (ductus choledochus). For up to 8 weeks of gestation, the extrahepatic biliary tree further 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. These observations disprove the long-held concept that there is a “solid stage” of entodermal occlusion of the common bile duct lumen and hence refute the concept that extrahepatic bile duct atresia may be caused by failure of recanalization of the common bile duct (Tan and Moscoso,1994b).

At 29 days after fertilization, the gallbladder anlage is visible as a right anterolateral dilatation along the distal half of the hepatic diverticulum, with a cystic duct present at 34 days. At that stage, the gallbladder and cystic duct are provided with a lumen (Tan and Moscoso,1994b). Outpockings appear in the gallbladder wall in the 42-mm embryo; folds develop on the interior surface of the bladder at the 78-mm stage (Dubois,1963). The outer layers of the gallbladder and cystic duct develop from condensing mesenchyme around the original epithelial mass. Myoblasts develop around the 30-mm stage, resulting in the establishment of all three layers of the wall of the future gallbladder: the mucosa, the muscular layer, and the serosa. From 11 weeks of gestation onward, the gallbladder epithelium reacts with a monoclonal antibody directed against a 40-kDa epithelial autoantigen in ulcerative colitis, which simultaneously also appears in the gut and the skin (Das et al.,1992).

The mRNA of the onecut transcription factor HNF6 is expressed in mouse liver from the onset of its development, and is detected not only in hepatoblasts (see further) but also in the extrahepatic bile ducts and the gall bladder primordium (Landry et al.,1997; Rausa et al.,1997).

In the mouse, development of the gallbladder further requires normal functioning of the forkhead box f1 gene (foxf1 gene). Haploinsufficiency of the Foxf1 transcription factor results in gallbladder malformation, with inadequate external smooth muscle layer, insufficient mesenchymal cell number, and in some cases absence of a discernable cholangiocytic mucosal lining (Kalinichenko et al.,2002).

The caudal pars cystica of the hepatic diverticulum is associated closely with the ventral pancreatic bud. The portion of the hepatic diverticulum between the cystic duct and the gut (the choledochus) increases in length and a localized outgrowth develops from its dorsal wall: the ventral pancreas (Severn,1972).

The pars cystica of the hepatic diverticulum begins initially from the anterior side of the future duodenum. Approximately the fifth week, the duodenum rotates to the right, so that the attachment of the developing common bile duct becomes displaced to its definitive position on the dorsal side of the duodenum (Dubois,1963).

The hepatic duct (ductus hepaticus) develops from the cranial part (pars hepatica) of the hepatic diverticulum. For a long time, the development of the proximal branches of the hepatic duct was not well understood (Jorgensen,1977). The detailed investigations by Tan and Moscoso (Tan and Moscoso,1994a; Tan et al.,2002) have documented this part of development.

In the 34-day embryo, the common hepatic duct is a broad, funnel-like structure in direct contact with the developing liver, without a recognizable left or right hepatic duct. During the fifth week, a rapid entodermal proliferation takes place in the dilated funnel-shaped structure above the junction of common bile duct and cystic duct; this proliferation gives rise to several folds, resulting in several channels at the porta hepatis (Tan and Moscoso,1994a; Tan et al.,2002). It is speculated that this remodeling at least partially explains the existence of the several normal variants in the configuration of the right and left hepatic ducts. The “normal” Y-shaped junction of right and left hepatic ducts with the common bile duct is found in only 57% of adults (Tan and Moscoso,1994a). 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 (Tan et al.,2002). The extrahepatic bile ducts and the developing intrahepatic biliary tree maintain luminal continuity from the very start of organogenesis throughout further development (Tan et al.,2002), 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 (Shiojiri and Katayama,1987).

Hes 1, the protein product of the Hes 1 gene is expressed in the epithelium of the extrahepatic bile ducts throughout their development. In vivo loss of Hes 1 (a transcription factor directly regulated by the Notch signalling pathway) results in agenesis of the gallbladder and hypoplasia of the extrahepatic bile ducts (Mahlapuu et al.,2001).

DEVELOPMENT OF INTRAHEPATIC BILE DUCTS

During the first 7 weeks of embryonic life, there is no intrahepatic bile duct system in the developing liver (Bloom,1926; Elias and Sherrick,1969). Different investigators have given varying reports of the precise moment of its first appearance. Its formation sets in at approximately the 18-mm (Elias and Sherrick,1969; Jorgensen,1977; Ruebner et al.,1989) to 22-mm (Bloom,1926) stage or between the fifth and ninth gestational weeks (Dubois,1963). A recent study mentions the seventh week as the time point for the first appearance of the intrahepatic bile duct system and describes a junction between the extrahepatic bile ducts and the earliest intrahepatic bile duct structure at the time of its first appearance in the liver hilum (Ruebner et al.,1990; Blankenberg et al.,1991).

Several theories exist about the development of the intrahepatic bile ducts. One theory maintains that the intrahepatic biliary tree is derived from ingrowth of the epithelium of the extrahepatic ducts (Hammar,1926). Another postulates that the entire intrahepatic bile-draining system develops from hepatocyte precursor cells (hepatoblasts; reviewed in Desmet,1999). A third theory combines elements of both of the first two. Most investigators favor the second hypothesis. This concept was based on routine light microscopic and ultrastructural investigations.

The hepatoblastic origin of the intrahepatic bile duct system received additional support from several studies that reinvestigated the embryologic development of the intrahepatic bile ducts with immunohistochemical techniques (Moll et al.,1982; Van Eyken et al.,1987; Van Eyken et al.,1988; Desmet et al.,1990; Ruebner et al.,1990; Stosiek et al.,1990; Blankenberg et al.,1991; Tan and Moscoso,1994a; Haruna et al.,1994; Vijayan and Tan,1997; Faa et al.,1998; Desmet,1999; Tan et al.,2002). These studies made use of immunohistochemical stains for cytokeratins, tissue polypeptide antigen, carcinoembryonic antigen, epithelial membrane antigen, and other markers for parenchymal and bile duct cell phenotypes. However, lineage studies that firmly establish the hepatoblastic origin of the bile duct lining cells have not yet been performed. Newer techniques, like targeted somatic gene rearrangements using the Cre recombinase in transgenic mice might solve the problem (Lemaigre,2003).

Immunostaining for cytokeratins has been particularly useful for revealing changes in cellular phenotype. Cytokeratins are the intermediate filaments of the cytoskeleton characteristic for epithelial cells. Different cytokeratins have been identified and catalogued (Moll et al.,1982). Normal adult human liver parenchymal cells express only the cytokeratins 8 and 18; intrahepatic bile duct cells express in addition the cytokeratins 7 and 19 (Van Eyken et al.,1987) and 20 (Faa et al.,1998).

In its earliest developmental stages, the human embryonic liver is composed of epithelial liver cell precursors (hepatoblasts) that express the cytokeratins 8, 18, and 19 (Desmet et al.,1990; Stosiek et al.,1990), and in addition cytokeratin 14 from 10 to 14 weeks of gestation (Haruna et al.,1994; Table 1). The development of the intrahepatic bile ducts is determined by the development and branching pattern of the portal vein, starting at the hilum of the liver.

Table 1. Cytokeratins for probing cell lineage relationships in developing liver
original image

Around the eighth week of gestation, the primitive hepatoblasts adjacent to the mesenchyme around the largest hilar portal vein branches become more strongly immunoreactive for their cytokeratins 8, 18, and 19. This layer of cells, surrounding the portal vein branches like a cylindrical sleeve, is termed the ductal plate (Van Eyken et al.,1988), in analogy to the terminology of Hammar (1926; Fig. 1). Recent studies unraveled that biliary cell differentiation is induced in the fetal liver by a periportal gradient of activin/transforming growth factor-beta (TGFβ) signaling, the extent of which is controlled by the inhibitory influence of HNF6 and the Onecut factor OC-2. The Notch pathway may act in parallel or downstream of the activin/TGFβ signaling to further support the biliary differentiation or to repress the hepatocytic differentiation program in these cells (Clotman et al.,2005). The results of a study in murine liver indeed suggest an inhibitory role of Notch1 on hepatocellular proliferation (Croquelois et al.,2005).

Figure 1.

The ductal plate is the layer of cells surrounding the portal vein and branching like a cylindrical sleeve.

In mice, the Forkhead Box m1 transcription factor (Foxm1b) is also essential for normal intrahepatic bile duct cell differentiation, besides development of vessels and sinusoids (Krupczak-Hollis et al.,2004). The ductal plates adjacent to the mesenchyme (the portal ductal plate layer) become duplicated by a second layer of more keratin-rich cells over variably long segments of their perimeter (the second or lobular ductal plate layer; Blankenberg et al.,1991). During the following weeks, ductal plates also appear around the smaller portal vein branches at a distance from the hilum. In the meantime, the hepatoblasts not involved in ductal plate formation gradually lose cytokeratin 19, and by 14 weeks of gestation the future parenchymal cells are immunoreactive only for cytokeratins 8 and 18, the cytokeratin pair normally expressed in adult liver parenchymal cells.

From approximately 12 weeks of gestation onward, a progressive “remodeling” of the ductal plates takes place, starting again in the earliest ductal plates around the larger portal vein branches near the hilum. Over short segments of the perimeter of the double-layered ductal plates, a “tubular” dilatation occurs of the slit-like lumen, lined now by taller keratin-rich cells (Fig. 1). These cells acquire epithelial membrane antigen and lose their biliary glycoprotein I (Blankenberg et al.,1991). The “tubular” parts of the ductal plate become incorporated into the mesenchyme surrounding the portal vein (the future portal tract) by ingrowth of mesenchyme between the lobular ductal plate layer and the hepatoblasts. The tubules incorporated into the portal mesenchyme are the future portal ducts; they remain connected, however, to the ductal plate and its adjacent parenchyma by thin epithelial channels, assuring continuity between the portal ducts and the already developed canalicular network located between the primitive hepatocyte precursor cells. Most of the excess epithelial components of the ductal plate that are not involved in tubule formation gradually disappear (Desmet,1999). The ramification of the biliary tree continues throughout fetal life toward the liver periphery, but with a “slow-down period” of the progressive ramifications between the 20th week and the 32nd week of gestation when the intraportal granulopoiesis of the liver is active (Sergi et al.,2000).

By 20 weeks of gestation, weak immunoreactivity for cytokeratin 7 appears in the cells of the developing ducts, again appearing first in the older ducts near the hilum (Van Eyken et al.,1988). The immunoreactivity for cytokeratin 7 gradually increases and extends into more peripheral ducts, to reach the level of immunoreactivity observed in ducts of the adult liver at approximately 1 month after birth (Van Eyken et al.,1988). Other phenotypic markers appearing in the ducts include epithelial membrane antigen and carcinoembryonic antigen (Blankenberg et al.,1991).

At the time of birth, the most peripheral branches of the intrahepatic biliary tree are still immature: The finest portal vein radicles still are surrounded by ductal plates, which require an additional 4 weeks after birth to develop into small portal ducts (Blankenberg et al.,1991). This finding indicates some degree of immaturity and incompleteness of the intrahepatic bile duct system in the neonate and may explain the lower ratio of the total number of bile ducts to the total number of portal tracts in premature infants (Kahn et al.,1989).

The factors determining the developmental fate of the bipotential hepatoblasts remain incompletely known. There is evidence that components of the portal mesenchyme are crucial for inducing the phenotypic shift into bile duct-type cells in the layers of the ductal plate (Doljanski and Roulet,1934).

Several components, including laminin, fibonectin, collagen types I and IV, expression of corresponding cellular integrins, catenin, and N-CAM have all been shown to be involved (for review, see Lemaigre,2003).

The process of intrahepatic bile duct development comprises schematically the following components: (a) a gradual phenotypic change of the hepatoblasts toward bile duct type cells; (b) a remarkable remodeling of the tridimensional structure of the ductal plate; and (c) an ongoing further maturation of the remodeled, tubular ducts (reviewed in Balistreri,1991; Desmet,1995,1999; Nakanuma et al.,1997; Terada et al.,1997; Roskams et al.,1998).

The phenotypic change from hepatoblast to cholangiocyte consists of a complex series of expressions of new molecules, including the de novo expression not only of cytokeratin 7 but also other molecules like carcinoembryonic antigen and epithelial membrane antigen, successively changing expression of surface glycoproteins and of glutathione S-transferase π, switching expression of integrins (loss of α1, induction of α6, and de novo expression of β4, α2, and α3 chains; Couvelard et al.,1998) and varying expression of the Ca2+-dependent cell adhesion molecule epithelial cadherin and the linked cytosolic components α- and β-catenin (Terada et al.,1998). The homeobox transcription factor Prox1 remains highly conserved in embryonic hepatoblasts, but is absent in bile duct epithelium (Dudas et al.,2004). The C/EBP α (CCAAT/enhancer-binding protein-α), which is expressed in hepatoblasts from the early stage of hepatic specification, is not observed in cholangiocytes of extra- and intrahepatic bile ducts (Shiojiri et al.,2004).

The remodeling of the ductal plate involves epithelial changes—construction of new epithelial structures (by proliferation) and the simultaneous deletion of other parts (by apoptosis), mesenchymal influence, and determination by the portal vein. Autocrine stimulation of ductal plate cell proliferation is suggested by the immunohistochemical positivity for transforming growth factor-α, hepatocyte growth factor, and parathyroid hormone-related peptide. Apoptosis in the remodeling ductal plate is indicated by positive histochemical terminal deoxynucleotidyl transferase mediated bio-deoxy UTP nick end labeling (TUNEL) staining and expression of Fas, C-myc, and Lewisy.

The importance of the periepithelial mesenchyme is indicated by the topographic expression of laminin and collagen type IV, and the matrix glycoprotein tenascin for the larger intrahepatic bile ducts; the expression of matrix metalloproteinases (MMP1) and their inhibitors (TIMP1 and TIMP2; Quondamatteo et al.,1999); patchy expression of N-CAM (Neural Cell Adhesion Molecule) in duplicated ductal plates and incorporating ducts, and denser cellularity and nerve fibers close to incorporating ducts(Libbrecht et al.,2001).

The determining influence of the portal vein is evident from the exclusive development of intrahepatic bile duct structures around the branches of this afferent vessel (Shiojiri and Nagai,1992). The further maturation of the remodeled tubular ducts comprises, among others, a switch from apomucin MUC1 to MUC3, the further development of the peribiliary capillary plexus, and—for the larger intrahepatic bile ducts—the development of their peribiliary glands (Nakanuma et al.,1997).

There is a close interaction of the developing intrahepatic bile ducts not only with the portal mesenchyme, but with the developing hepatic artery as well (arterial–ductal interaction). The sequence of events indicates that the ductal plates precede and determine the development of the intrahepatic branches of the hepatic artery. The appearance of α-smooth muscle actin positive myofibroblasts and their organization into a vascular wall (vasculogenesis) follows the development of ductal plates (Libbrecht et al.,2002). The developing arterial branches in turn precede and presumably induce, during the remodeling process, the incorporation of the peripheral biliary cell tubules, which are accompanied by a denser myofibroblastic cell population which gives rise in turn to the peribiliary vascular plexus (Terada and Nakanuma,1993b). The dependence of arterial development on normal progression of bile duct development entails an involvement of the transcription factors HNF6 and HNF1β for both structures (Clotman et al.,2002,2003; Coffinier et al.,2002). The arterial – ductal interaction is also reflected in the involvement of the same signaling pathways (Jagged 1 / Notch) in the development and in the maintenance of both the hepatic arterial system (Xue et al.,1999; Crosnier et al.,2000) and of the intrahepatic biliary tree (Louis et al.,1999; McCright et al.,2002; Nijjar et al.,2002; Flynn et al.,2004; Kodama et al.,2004). Differences in the human and murine expression patterns for Jagged and Notch preclude at present a detailed mechanistic insight into the precise role of this pathway in bile duct development (Lemaigre,2003).

It thus appears that, in the embryological development of the liver, it is the portal vein that determines the three-dimensional structure of the ramifying portal tracts and their essential tubular components (portal vein, bile duct, and hepatic artery), which constitute the basic angioarchitecture of the liver and its lobular organization.

POSTNATAL DEVELOPMENT OF THE INTRAHEPATIC BILE DUCTS

The intrahepatic biliary system in not mature at the time of birth. During human fetal development, the major canalicular transporter genes are expressed at mid-gestational age, but differ in expression level and targeting pattern, indicating differential regulation and maturation (Chen et al.,2005). Bile canaliculi between hepatocytes only acquire a mature appearance at the perinatal and early postnatal period (De Wolf-Peeters et al.,1974; Kanamura et al.,1990).

The remodeling of the intrahepatic bile ducts is not complete at the time of birth; it requires approximately 6 additional weeks for the ductal plates in the most peripheral (smallest) portal tracts to remodel (Van Eyken et al.,1988). This has implications for defining the “normal” bile duct-to-portal tract ratio (BD/PT ratio), which is used to estimate the degree of ductopenia in the liver. A BD/PT ratio lower than 0.9 may be normal in the premature infant (Van Eyken et al.,1988; Kahn et al.,1989; Sergi et al.,2000).

The expression of ParaThyroid Hormone-related Peptide (PTHrP) by cholangiocytes remains positive until the age of 4 years (Roskams and Desmet,1994). The end-stage maturity of the hilar peribiliary glands (Terada and Nakanuma,1993a) and of the peribiliary capillary plexus (Terada and Nakanuma,1993b) is only reached at the age of 15 years. Liver mass increases from 125 g at birth to 255 g at 1 year of age, 430 g at 2 years, and 530 g at 5 years. The adult liver weighs approximately 1,400 g, more than 10 times the weight of the newborn liver (Shankle et al.,1983; Crawford,2002). There is only scanty information on the structural and lobular development of the human liver from birth to adulthood, possibly related to the unending search for the identity of the structural and functional unit of the liver: the classic lobule (Kiernan,1833), the portal lobule (Mall,1906), the acinus (Rappaport,1973), the metabolic lobulus (Lamers et al.,1989), the primary and composite lobule (Matsumoto et al.,1979; Matsumoto and Kawakami,1982), its modular variant (Teutsch,2005), and the smallest unit termed “choleohepaton” (Ekataksin and Wake,1997). An old investigation indicated that, in the pig, the liver mass increases through increase in size and in number of the liver lobules, which themselves increase in size through increase in size and number of their constituting hepatocytes (Johnson,1919). Consequently, also the intrahepatic biliary tree is growing after birth. Landing and Wells propose, on the basis of observation and assumptions, that postnatal human liver growth occurs by an increase in number of peripheral lobules associated with branching and elongation of the accompanying portal tracts (Landing and Wells,1991).

In the adult liver, the complete sequence of intrahepatic bile ducts from the hepatic ducts to the smallest ductules, as demonstrable on cholangiographic documents, comprises 11 to 12 orders of branching (Ludwig et al.,1998), but cholangiography fails to visualize an unknown number of finer ramifications. It is estimated that, in the adult liver, the biliary tree requires between 18 and 20 orders of branches to realize the ± half million terminal bile ducts, necessary to assure biliary drainage of the estimated 440,000 microarchitectural units (defined as lobules or otherwise; Crawford,2002). Because bile duct branching occurs in a three-dimensional tree-like manner, small (“peripheral”) branches in small (“peripheral”) portal tracts are formed not only in the hepatic periphery but also within the liver, just as terminal twigs and leaves are also found inside the crown mass of a tree (Landing and Wells,1991).

Because shortly after birth ductal plates composed of immature cholangiocyte precursor cells have disappeared, and new bile ducts apparently arise from preexisting mature, tubular ducts by branching and elongation. This has been compared with blood vessel development: formation from immature cells is referred to as “vasculogenesis,” whereas growth of preexisting vessels by sprouting is termed “angiogenesis.” In a similar way, it is suggested that “ductogenesis” and “cholangiogenesis” could be used as respective Latin- and Greek-derived terms to refer to bile duct formation before and after birth respectively (Libbrecht et al.,2002).

In human liver, Jagged1 is expressed in bile duct cells, hepatocytes, and vasculature, with, however, some variation between different reports (Louis et al.,1999; Nijjar et al.,2002). The immunohistochemical localization of Notch 1 and Notch 2 in mature bile duct cells of pediatric normal liver suggests that Notch signalling continues to play a role in bile duct growth and remodeling in postnatal life, albeit that the precise tuning of the signalling may differ from what happens during development, because in the fetal liver, the ductal plate cells express Jagged1, and Notch3 protein is found in the closely adjacent mesenchymal cells (Flynn et al.,2004). The results of a study in mice on inducible inactivation of Notch 1 point to a critical role of Notch 2, and not of Notch 1, for the maintenance of bile duct integrity (Croquelois et al.,2005). One has to keep in mind that the modalities of Notch signalling are not a linear picture; each step is subject to additional elements and features that modulate the activity and efficacy of the transmitted signals, and is further influenced by the developmental context (Artavanis-Tsakonas et al.,1995,1999).

The terminology of the adult intrahepatic bile duct system has recently been standardized by a consensus effort (Roskams et al.,2004).

DUCTAL PLATE MALFORMATION (DPM)

The normal development of intrahepatic bile ducts apparently 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 (DPM; Jorgensen,1977). Hnf6−/− and Hnf1β−/− mouse embryos show abnormal intrahepatic bile ducts corresponding to DPM, revealing the importance of the HNF6-HNF1β cascade in normal development of the intrahepatic bile ducts (Clotman et al.,2002; Coffinier et al.,2002), as mentioned above (see Development of intrahepatic bile ducts).

Ductal plate malformation originally referred to a microscopic lesion (Jorgensen,1977). Modern imaging techniques of the liver, however, such as ultrasonography and computed tomography, which produce the equivalent of sections through the liver, allow visualization of the abnormalities of DPM also in the larger branches of the intrahepatic biliary tree (Marchal et al.,1986; Inui et al.,1992; Van Eyken and Desmet,1992; Levy and Rohrmann,2003; Zeitoun et al.,2004; Brancatelli et al.,2005).

Lack of remodeling of the ductal plate (or DPM) appears to be associated often with abnormalities in the branching pattern of the portal vein. Instead of giving rise to a regular, tree-like branching pattern, resulting in individual portal tracts separated by intervening parenchyma, as occurs in the normal liver the involved portal vein branch gives rise to multiple sprouts with diameters too small and spaced too closely together, resembling the branches of a “pollard willow” (Desmet,1992a,b).

Lack of remodeling of the ductal plate (or DPM) appears to be associated often with abnormalities in the branching pattern of the portal vein. Instead of giving rise to a regular, tree-like branching pattern, resulting in individual portal tracts separated by intervening parenchyma, as occurs in the normal liver the involved portal vein branch gives rise to multiple sprouts with diameters too small and spaced too closely together, resembling the branches of a “pollard willow” (Desmet,1992a,b).

A transverse section through such a pollard willow appears as an enlarged portal area, which corresponds to the fusion of several smaller portal tracts, each containing a ductal plate (or incompletely remodeled parts thereof) surrounding a hypoplastic or even obliterated branch of the portal vein (Desmet,1992a,b).

Ancillary