Special Article Congenital Diseases of Intrahepatic Bile Ducts: Variations on the Theme “Ductal Plate Malformation” VALEERJ. DESMET University Hospital Sint Rafad, K . U. Leuven, Laboratory of Histochemistry and Cytochemistry, B-3000Leuven, Belgium

Congenital diseases of intrahepatic bile ducts (IHBDs) can be divided into two main groups: diseases characterized by necroinflammatory destruction of IHBDs and diseases characterized by a variable degree of ectasia of IHBDs and associated with a variable degree of fibrosis. This review will emphasize that in most - if not all-of these conditions, persistence or lack of remodeling of the embryonic ductal plate (so-called “ductal plate malformation” [DPM]) is an essential precursor of the lesions (1). EMBRYOLOGY OF IHBDs AND DPM

During the fourth week of human gestation, the liver arises as a bud of cells (the hepatic diverticulum) from the ventral wall of the most cephalad portion of the foregut, near the junction with the yolk sac (2). In the human, as in the mouse, the hepatic diverticulum comprises two parts: a pars cranialis or pars hepatica and a pars caudalis or pars cystica. The former gives rise to liver precursor cells that grow into the mesenchyme of the septum transversum, which consists of a mass of loosely arranged mesodermal cells separating the pericardial and peritoneal cavities. The caudal part of the hepatic diverticulum develops into the gallbladder and the common bile duct. The cranial or hepatic part of the diverticulum acquires a T-shaped cephalic end, with more pronounced growth of epithelial sprouts from the lateral walls, creating the early outline of the right and left lobes of the liver. The liver precursor cells grow between small endothelium-lined spaces in the septum transversum that connect with the capillary plexus of the vitelline (or omphalomesenteric) veins, thus establishing the basic architecture of liver parenchyma: parenchymal cords and plates alternating with hepatic sinusoids. During the first 7 wk or so of embryonic life, no intrahepatic bile duct system exists in the developing liver. Its formation begins around the eighth gestational week.

Received March 15, 1992; accepted June 8. 1992. Address reprint requests to: Prof. Dr. V.J. Desmet, Universitair Ziekenhuis Sint Etafael, Laboratorium voor Histochemie and Cytochemie, Minderbrdersstraat 12, B-3000 Leuven, Belgium.

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Several theories have been advanced on the development of the IHBD. One theory maintains that IHBDs are derived from ingrowth of the epithelium of the larger hilar duct structures (3). The second theory postulates that the entire intrahepatic biliary system is derived from hepatocyte precursor cells, which transform into ductules and ducts to join the extrahepatic biliary bud at the hilum (2).A third theory combines elements of the first two theories. Most authors favor the second hypothesis. Until recently, this theory derived its main support from routine light microscopic and ultrastruct u r d observations. In recent years, several immunohistochemical studies have reinvestigated the embryological development of IHBDs; all support the “hepatocytic” origin of IHBDs (4-13).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 cells. Cytokeratin studies have been particularly useful in identifying cellular phenotypes. Cytokeratins are the intermediate filaments of the cytoskeleton characteristic of epithelial cells. Nineteen different cytokeratin polypeptides have been identified and cataloged by Moll et al. (14). Normal adult human liver parenchymal cells express only the cytokeratins 8 and 18, whereas intrahepatic bile duct cells express in addition the cytokeratins 7 and 19. In its early stage of development, the embryonic liver is composed of epithelial liver cell precursors (progenitor cells or hepatoblasts), which express the cytokeratins 8, 18 and 19 (6, 11). Around the eighth week of gestation, the liver precursor cells located around the largest portal vein branches become more strongly immunoreactive for these three cytokeratins. This layer of cells, surrounding the portal vein branches like a sleeve, is referred to as the “ductal plate” (12) (Figs. 1 and 2). The ductal plates are duplicated by a second layer of more keratin-rich cells over variably long segments of their perimeter. In the following weeks, ductal plates also appear around the smaller portal vein branches distal to the hilum. In the meantime, the cells not involved in ductal plate formation gradually lose cytokeratin 19; after 10 wk of gestation they are only immunoreactive for cytokeratins 8 and 18 (the cytokeratin pair normally present in adult liver parenchymal cells).

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FIG. 1. Embryonic d u d plate in 18-wk-old fetal liver. The portal vein (PV) and its surrounding mesenchyme are encircled by a layer of primitive hepatic precursor cells,which show small cell volume and increased expression of cytokeratins (dark stain). This layer appears doubled in some parts of the portal perimeter (arrows).In this ductal plate, one tubular structure (future interlobular d u d ) is already formed (arrowhead).Note the weaker expression of cytokeratins in the primitive parenchymal precursor cells, which are not adjacent to the portal mesenchyme. Hematopoietic cells appear as dark dots between the parenchymal precursor cells (immunostaining with monoclonal anticytokeratin antibody KL-1 [Immunotech, Marseille, France1 and counterstaining with hematoqlin; original magnification x 312). Specimen is courtesy of Dr. P. Moerman, Leuven, Belgium.

Ductal Plate

Remodeling of Ductal Plate

FIG. 2. Schematic representation of the embryonic ductal plate and its remodeling into the mature tubular ducts of the portal tract. For description, see text. Compare with Figure 1.

From about 12 wk of gestation on, a progressive “remodeling” of the ductal plates takes place, starting again in the oldest ductal plates around the larger portal vein branches near the hilum (Figs. 1 and 2). Short segments of the double-layered ductal plate dilate to form tubular structures (Fig. l),which are subsequently incorporated as individualized bile duct tubes into the mesenchyme surrounding the portal vein branches. Around 20 wk of gestation, weak immunoreactivity for cytokeratin 7 appears in the bile ducts, first in the larger ducts near the hilum. The immunoreactivity for cytokeratin 7 gradually increases to reach the level observed in adult liver at about 1mo after birth (6, 12). Other markers in the developing bile ducts include carcinoembryonic antigen and epithelial membrane antigen (4). At the time of birth, the most peripheral portal vein

branches are not yet accompanied by an individualized bile duct, but are still surrounded by a layer of cytokeratin-rich cells in ductal plate arrangement. This indicates some degree of immaturity and incompleteness of the intrahepatic bile duct system at birth (12). In short, intrahepatic bile duct cells develop from the precursor cells surrounding the portal vein branches; this development is characterized by increased expression of cytokeratins 8, 18 and 19, followed by expression of cytokeratin 7 and other differentiation markers. In contrast, parenchymal cells develop from the precursor cells not in contact with the perivenous mesenchyme by losing cytokeratin 19, at the same time acquiring further parenchymal cell markers. The factor or factors determining the developmental fate of the liver precursor cells remains largely unknown. However, evidence indicates that components of the mesenchyme surrounding the portal vein branches play a crucial role in inducing the biliary differentiation of the ductal plate cells (10, 12, 15). A similarly crucial role of the mesenchyme is presumably involved in the remodeling of the ductal plate, which includes tubular dilatation of segments of the ductal plate, incorporation of the tubular parts into the portal mesenchyme and the disappearance of most of the nontubular portions of the ductal plate. As in other fields of organogenesis, the normal development of IHBDs apparently requires finely and timely tuned epithelial-mesenchymal interactions, which proceed from the hilum of the liver toward its periphery along the branches of the developing portal vein.

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Ductal Plate Malformation

FIG. 4. Schematic drawing of the appearance of the DPM as it appears on liver imaging techniques and in microscopic liver sections. (Left)Lack of remodelingof the ductal plate, which appears as a dilated duct containing a fibrovascular axis in its lumen. (Middle and right) Incomplete remodeling of the ductal plate, which appears as an interruptedcircle of curved bile duct profiles (middle) or as a polypoid projection in a dilated duct (right).Compare with figures 3 , 7 , 8 , 1 0 , 11 and 12.

nants of incompletely remodeled ductal plates) surrounding several hypoplastic or even obliterated portal vein branches (Figs. 5 and 6). In short, three main points are important for the discussion of DPM as a basic component in congenital diseases of the IHBDs: (a) the different segments of the intrahepatic biliary tree (larger ducts, segmental and area ducts, interlobular ducts and smallest bile duct FIG. 3. Ultrasonography of the liver in a child with Caroli’s ramifications) develop during successive periods in fetal syndrome. The image shows IHBDs with local, saccular dilatation. life; (b) DPM can be observed in larger and in smaller Note the intraductal polypoid projection (arrow), which contains a IHBDs; and ( c )DPM is often associated with abnormalsmall portal vein branch (DPM). Compare with right-hand panel of ities in the ramification pattern of the portal vein, giving Figure 4. Photograph is courtesy of Prof. G. Marchal, Leuven, rise to too many, too-small and too closely spaced Belgium. branches in that area (pollard willow formation). BILE DUCT ATRESIA

Lack of remodeling of the ductal plate results in the persistence of an excess of embryologic bile duct structures in ductal plate configuration, or DPM (16). “DPM” originally referred to a microscopic lesion (16).However, modern imaging techniques of the liver such as ultrasonography and computer-assisted tomographic scans, which produce the equivalent of sections through the liver, also allow visualization of the abnormalities of DPM in larger branches of the IHBDs (17-20)(Fig. 3). Basically, DPM appears in cross section as a circular lumen containing a fibrovascular axis in the center (in cases of complete lack of remodeling of the ductal plate). Incomplete remodeling may give rise to a ring of interrupted lumina around a central fibrovascular axis or to images depicting a grossly dilated duct containing a polypoid projection (Fig. 4). Lack of remodeling of ductal plates appears to be frequently associated with abnormalities in the ramification pattern of the portal vein. Instead of developingin the normal treelike branching fashion, which results in individual portal tracts separated by intervening parenchyma, the involved portal vein branch gives rise to several sprouts that have too-small diameter and are spaced too closely together, comparable to a pollard willow (a tree cut back to the trunk to encourage dense growth of foliage) (2, 21-23).A transverse section through such a “pollard willow” area will appear as an enlarged portal tract (in fact, it is a fusion of several portal tracts) containing several ductal plates (or rem-

Extrahepatic Bile Duct Atresiu. Extrahepatic bile

duct atresia (EHBDA)does not represent agenesis of the bile ducts, but results from progressive destruction of the bile ducts by a necroinflammatory process of unknown etiology (22).In spite of the classic terminology, this destructive and sclerosing form of cholangitis affects not only part or all of the extrahepatic ducts, but also the intrahepatic branches of the biliary tree, leading to paucity of interlobular ducts, or ductopenia (22). It is of interest that in some 20% to 25% of cases of EHBDA, the interlobular ducts still appear in their primitive embryonic shape (DPM) (1,22,24, 25) (Figs. 6 and 7). This observation suggests that the causative factor of atresia starts early in fetal life in these cases, at the time that the IHBDs are still in ductal plate configuration. An early antenatal start of the disease might explain the often advanced degree of fibrosis observed in liver biopsy specimens of these infants even at the very young age of 30 days. For this reason, this subgroup of patients with EHBDA and DPM of the interlobular bile ducts has been designated as having “early severe” EHBDA (22). Hepatic portoenterostomy -the Kasai operation- has become the treatment of choice for EHBDA. However, long-term follow-upof patients reveals that this surgical reconstruction of bilioenteric continuity does not result in definite cure in most patients (22, 26). Hepatic portoenterostomy relieves the extrahepatic obstruction

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Normal branching pattern o f portal vein

”Pollard willow“ branching pattern

FIG.5. Schematic drawing representing the normal branching pattern of the portal vein (left)and a pollard willow pattern (right).For explanation, see text. The circlesaround the cross sectioned portal vein branches can be viewed both as portal tracts and as possible profiles of biliary ductal plates. Compare with figures 6, 10, 12 and 13.

and thus saves the patient from rapid progression to biliary cirrhosis, but the reestablishment of bilioenteric continuity does not by itself cure the basic disease process, which also destroys the IHBDs. In some, this intrahepatic destructive cholangitis is rapidly progressive and in others slow; in a few patients it seems to burn out, resulting in real cure (22). An interesting observation was made in a study of children several years after successful hepatic portoenterostomy (27). In children who displayed ductal plate configuration of the interlobular bile ducts at the time of portoenterostomy, follow-up liver biopsies after four to five nearly symptom-free years revealed a histopathological picture closely resembling that of congenital hepatic fibrosis (CHF) (22, 27) (Fig. 8). This lesion was interpreted as a fetal type of biliary fibrosis (22). Close analysis revealed features of mild but ongoing bile duct destruction, suggesting a persistence of the basic disease process of EHBDA, albeit at a very slow rate (22,23,25).This remarkable observation indicates that a neonatal disease process, characterized by destruction of immature bile ducts (early severe EHBDA), may result in a histopathological lesion indistinguishable from congenital hepatic fibrosis, provided that the patient is given the chance to survive long enough with hepatic portoenterostomy. It raises the suspicion that a “spontaneously abortive” or “self-healing” form of bile duct damage might lead to similar sequelae and thus that congenital hepatic fibrosis might be the result of an arrested or mild form of destruction of immature interlobular ducts (25) (see below). Paucity of Interlobular Bile Ducts. Clinically, two categories of paucity of interlobular bile ducts are recognized: syndromic (Alagille’s syndrome) and nonsyndromic (28,29).The basic lesion is a destructive form of cholangitis resulting in a reduced number of interlobular ducts (paucity or ductopenia). Whether DPM is also seen in syndromic or nonsyndromic variants of paucity of interlobular bile ducts has not been reported. This subject warrants further study.

Liver diseases characterized by some degree of dilatation of segments of the IHBDs associated with fibrosis (fibrocystic diseases) constitute a merging spectrum of alterations. Usually they are associated with kidney abnormalities, which also represent a continuous spectrum of lesions. Some of the older literature on these associated congenital liver and kidney lesions is confusing because of changes in classification (especially of cystic kidney lesions). For instance, Caroli (30) described the pathological condition that carries his name (Caroli’s disease) as being associated with medullary sponge kidney or Cacci-Ricci disease. It must be recognized, however, that what is now termed Cacci-Ricci disease-medullary sponge kidney-is basically different from the kidney disease that usually accompanies Caroli’s disease (31). The abnormality that is the basic lesion in all variants of fibrocystic liver diseases is the DPM. DPM may affect all levels of the intrahepatic biliary tree: segmental ducts, septal ducts, interlobular ducts and the smaller ducts of the more terminal portal tract ramifications (Fig. 9). The DPMs at these different levels of the biliary tree determine the different anatomical-clinicalentities known under the designations Caroli’s disease, “infantile polycystic disease,” and “adult polycystic disease.” DPM involving all segments of the intrahepatic biliary tree causes the combination of these various anatomicalclinical entities; this has been described in several case reports (32, 33). DPM seems to often be associated with progressive destruction of these immature IHBDs by a nonspecific necroinflammatory process, which gives rise to the anatomical-clinical entities known as CHF and Caroli’s syndrome (Fig. 9). The liver lesions are associated with kidney abnormalities, which also may affect some or all levels of the nephron and which also may be accompanied by slow destruction of the involved tubular segments in a nonspecific necroinflammatory process (31). Autosomal Recessive Polycystic Kidney D i m . Because infantile polycystic disease (of liver and kidney) may also be observed in adults, the term “infantile polycystic disease” has been replaced by the more accurate designation “autosomal recessive polycystic kidney disease” (ARPKD) (31, 34). ARPKD is a rare disease, with an incidence between 1in 6,000 and 1in 40,000 births (34). It is inherited in an autosomalrecessive pattern. The gene mutation that causes the disease has not yet been identified (35). The animal model of ARPKD is the CPK mouse (a spontaneous mutation of the C57BL/6J mouse) (36). Different forms of ARPKD have been considered accordingto the age at presentation: perinatal, neonatal, infantile and juvenile (37).It remains uncertain whether the lethal neonatal form represents a genetic entity different from the form that affects children who survive until later in infancy (34). It remains equally unproven whether CHF involves the same genetic abnormality that causes ARPKD (34).

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FIG.6. Microphotograph illustrating an enlarged abnormal portal tract in the liver of a child aged 30 days with early severe EHBDA. T h s portal tract demonstrates (a) DPMs (around the connective tissue cores numbered 1, 2, 3, 4 and 5);(b) degenerative changes of the ductal epithelium, oocasional bile concrements in the lumina (near center) and mild inflammatory infiltration; and (c) the pollard willow pattern of fused portal tracts (indicatedby 1 , 2 , 3 , 4and 5).Note also the striking hypoplasia or disappearance of the portal vein branches. Often only arterial vessels are recognizable (HLE; original magnification x 125). Specimen is courtesy of Dr. F. Callea, Genoa, Italy.

FIG.7. Liver biopsy specimen from child aged 60 days with early severe EHFiDA. The bile ducts appear in ductal plate configuration; they show degenerative epithelial changes and mild inflammatory infiltration. Note the marked hypoplasia of the portal vein in the connective tissue core encircled by the ducts. (HLE; original magnification x 312). Specimen is courtesy of Dr.F. Callea.

For the purpose of this review and for reasons explained in the following discussion, ARPKD (comprising the perinatal, neonatal and infantile forms) will be considered separately from CHF (juvenile form of

ARPKD). The hepatic lesions in ARPKD are fairly uniform and

seldom give rise to macroscopically visible cysts. Microscopically, the liver is characterized by portal tracts that may be somewhat enlarged by connective tissue and contain numerous, somewhat dilated, bile duct profiles, corresponding to (more or less) incompletely remodeled ductal plates (DPM) (Fig. 10).Normal interlobular duds

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FIG.8. Liver biopsy specimen from a child, taken 4 yr after successful hepatic portoenterostomy for early severe EHBDA. The liver shows a congenital hepatic fibrosislike pattern. Large portal areas are joined by fibrous septa. This micrograph shows a greatly enlarged portal tract (in fact it is a fusion of portal tracts: compare with figures 5 and 6 ) containing several bile duct profiles in ductal plate configuration. Several bile duct segments (especially at right) appear involutive. Note the hypoplasia (or absence) of portal vein branches. Compare with figures 11 and 12 (H&E;original magnification x 125). Specimen is courtesy of Dr. F. Callea.

in the centers of the portal tracts are often absent. The number of bile duct profiles is variable, reflecting the variable degree of remodeling of the original embryologic ductal plate. These bile duct structures are in continuity with the rest of the biliary system (so-called communicating cystic disease) (38).Similar lesions of larger bile ducts (Caroli’s disease) may be associated (39).The renal lesions correspond to bilateral renomegaly, characterized by a fusiform dilatation of the collecting ducts; the affected part of the nephron thus corresponds to the division products of the ureteral bud and not to the later-developed products from the nephrogenic blastema (polycystic kidney of the type Potter I) (40). Neonates with the perinatal form of ARPKD die in the first few hours of life of pulmonary insufficiency. Babies with the neonatal and infantile forms of ARPKD, characterized by a lower percentage of affected collecting ducts, may survive for months or even years (34).In surviving children, progression of the liver and kidney lesions, with increasing amounts of fibrosis, seems to take place (41,42). With increasing age of the patient, a decrease in the number of ductular profiles and an increase in fibrosis of the portal tracts is often noted, whereas the renal cysts seem to become less numerous and more spherical and are associated with increasing interstitial fibrosis (43) approaching the appearance of medullary sponge kidney (31)or even that of adult polycystic disease (44). From the observations mentioned above, it can be proposed that the pathogenesis of ARPKD corresponds to a defect in epithelial-mesenchymal inductive interac-

tions, resulting in abnormalities of the renal collecting ducts and a more or less complete arrest of remodeling of the ductal plates during the development of the interlobular bile ducts. The latter would explain the possible absence of a mature bile duct in the center of the portal tract and the variable number of ductal profiles in its periphery (23, 25). The observation that this autosomal-recessive disease only affects the renal collecting ducts and not-or only to a lesser extent-the products of induction in the nephrogenic blastema may indicate that the causal hereditary factor has its influence only during an early period of embryological kidney development. The association of ARPKD with Caroli’s disease (see below) indicates an arrest of remodeling of the ductal plate not only during formation of the interlobular ducts, but also during an earlier stage when the larger segmental ducts are formed. The nonlethal forms of ARPKD (neonatal, infantile and juvenile forms) seem to be characterized by slow but progressive involution of renal and biliary epithelial tubes, followed by fibrous scarring. This mysterious process of necroinflammatory destruction of immature bile ducts and renal collecting ducts is the link with the next fibrocystic congenital liver disease: CHF (23,25). Congenital Hepatic Fibrosis. CHF (45) is an autosomal-recessive disease; in most cases it is associated with ARPKD (46). The liver abnormalities of CHF are also observed in other syndromes: Meckel-Gruber syndrome, Ivemark syndrome, Jeune syndrome, vaginal atresia and tuberous sclerosis (47,48).

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CHF may be associated with other liver malformations such as Caroli’s disease, von Meyenburg complex and choledochal cyst (32,33). The classic kidney lesion associated with CHF corresponds to ARPKD;however, cases have been described in which CHF was associated with adult polycystic disease (49, 50), with renal dysplasia (51) or with nephronophthisis (52). From the point of view of clinical symptoms, different forms of CHF are recognized: portal-hypertensive CHF, cholangitic CHF and latent forms of CHF (53). In view of such variable clinical expression, several authors have insisted that CHF does not constitute a single clinical entity but rather represents a full spectrum of liver and kidney lesions (44,54,55). In the simple form of CHF, the liver is of normal size without macroscopically visible cysts; it appears speckled, with irregular, whitish areas regularly distributed over the liver surface or on cut sections (56). The histopathological picture varies. In some patients, CHF is characterized by fibrous enlargement of the portal tracts, which contain variable numbers of abnormally shaped bile ducts (Figs. 11 and 12); in others, the liver shows bands of connective tissue of variable thickness linking adjacent portal tracts. Cases are on record with only partial involvement of the liver (e.g., one lobe) (57). The fibrous areas contain increased numbers of bile duct profiles, which have been shown to be in continuity with the rest of the biliary system (56). The portal vein branches are often hypoplastic (45,56) (Figs. 11 and 121,whereas the hepatic arterial branches may be supernumerous (56). Some investigators mention the existence of discrete signs of involution or epithelial degeneration of the aberrant bile ducts (16, 581, mild features of parenchymal cholestasis (58)and foci of ductular proliferation at the fibrous-parenchymal interface. Usually the latter features have been considered to be caused by bouts of cholangitis due to associated Caroli’s disease. The liver lesions of CHF may progress with time: in some patients, they remain relatively unchanged and in others the fibrosis may increase. Furthermore, the lesions may be modulated by superimposed bouts of cholangitis (42). The abnormal bile duct structures in CHF were recognized by Jorgensen (16)as corresponding to (more or less) incompletely remodeled ductal plates of interlobular bile ducts (Figs. 11 and 12). Sometimes duplications of ductal plates are seen, resulting in curved bile duct profiles arranged in concentric circles (59,60). Such duplication of ductal plates has been interpreted as a fetal type of ductular reaction (22). The observations on the multiple morphological appearances of CHF, on the evolution over time of the liver lesions in ARPKD (42)and on the CHF-like appearance of the liver &r successful portoenterostomy in early severe forms of EHBDA have led to the following hypothesis on the morphogenesis of CHF (25).

DPM + involution

DPM ectasia

von MEYENBURG

A.D.P.K.D.

complexes

A.R.P.K.D.

C.H.F.

CAROL1 disease

CAROL1 syndrome

I

FIG.9. Schematic representation of the biliary tree and the diseaaes discussed in this manuscript. The placement of diseases at different levels of the tree indicates the approximate size of the bile ducts affected by DPM in a particular disorder. The disorders mentioned on the left side are characterized by mild or marked dilatation of the bile duct structures, whereas the entities listed on the right develop with a variable degree of involution (“destructivecholangitis”)of the ductal plate remnants associated with fibrosis. Although intentionally ~ i m plified, this overview emphasizes the central theme discussed in this paper: that DPM is a basic feature of all congenital bile duct disorders mentioned.

The initial lesion of CHF corresponds to the liver lesion in ARPKD -that is, DPM of the interlobular bile ducts. The immature bile duct structures are subject to a slowly progressive process of destructive cholangitis resulting in gradual disappearance of bile duct profiles associated with increasing periportal fibrosis (Fig. 12). The rate and the duration of the destructive cholangitis are variable in individual patients (akin to the variations in the basic disease process of EHBDA after hepatic portoenterostomy). In some cases, it is rapidly progressive, in others it is slow and torpid and in still other patients it may burn out spontaneously (25). In this view, CHF corresponds to a fetal type of biliary fibrosis, which may be more or less advanced, still progressive or arrested. This hypothesis on the pathogenesis of CHF explains many reported observations: the variability in the time of appearance of clinical symptoms, the possible progression of the fibrous component of the lesion, the variability in the number of bile duct profiles observed, the reported hypoplasia of the portal vein, the sometimesreported features of ductal degeneration and involution, the small foci of ductular reaction, the possible signs of parenchymal cholestasis, the elevated levels of alkaline

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FIG.10. Autopsy liver specimen from full-term female infant who died of lung hypoplasia a few minutes after birth. The liver shows the typical bile duct pattern of ARPKD, with DPM of the interlobular bile ducts (appearing dark on immunostaining for cytokeratins). Note the hypoplasia (or absence) of portal vein branches in the fusing portal tracts. Compare with figures 7, 8 and 11 (immunostaining with monoclonal anticytokeratin antibody KL-1 [Immunotech]; original magnification x 125). Specimen is courtesy of Dr. P. Moerman.

FIG.11.Liver specimen from a 4-yr-old girl with congenital hepatic fibrosis. Note the broad bands of mature, collagenized connective tissue

and bile duct structures in ductal plate configuration.Portal vein branches are lacking in the central connectivetissue parts of the ductal plates. Compare with figures 7 , 8 and 10 (H&E; original magnification x 125).

phosphatase in the serum and the association of CHF with kidney lesions of ARPKD (25). Furthermore, this hypothesis draws a parallel between the epithelial destruction of the abnormal bile ducts and the epithelial involution of the abnormal renal tubules that is part of the progression of the kidney lesion (25,31,61>.

In this respect, one could conceive the association of CHF with nephronophthisis as a nosological variety in which the renal tubule destruction is more marked and more rapidly progressive (25). The hypothesis would further explain the cholestatic features (increased serum levels of bile acids) observed in some patients (62)

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FIG.12. Same liver biopsy specimen shown in Figure 11. Note the enlarged portal tracta (A, B), in which the ductal plate configuration of the bile ducts is less apparentthan in Figure 11. This is due to involution of the ductal plate remnants fl,2,3)in (A) (note the atrophicappearance of the bile duct segments) and to more pronounced remodeling of ductal plates in (B) (note the several short bile duct segments in circular arrangement in B1). Portal vein branches are hypoplastic or absent (H&E; original magnification X 125).

and the signs of chronic parenchymal cholestasis represented by cholestatic liver cell rosettes (although these are interpreted by the authors as signs of regeneration) (62). The cause of the biliary and renal epithelial involution remains unknown. A defect in the tubular basement membrane has been demonstrated (63).Apparently, the cause and the mechanism of bile duct destruction are M e r e n t from those in EHBDA and paucity of interlobular bile ducts because the latter diseases-in contrast to CHF-are not associated with kidney lesions. The association of CHF with Caroli’s disease and with adult type polycystic disease is discussed below. The association of CHF with abnormalities in other organs and systems can be explained by a variable duration of the action of the causative factor and by the temporal coincidence in the embryological development of different organs, among other factors (23,25). CAROLI’S DISEASE AND CAROLI’S SYNDROME

Caroli’s disease is a congenital dilatation of the larger (segmental) IHBDs (Figs. 3 and 9). Two varieties have been described (30):a pure form (Caroli’sdisease) characterized by ectasias of the IHBDs without further histological abnormalities and a combined form (Caroli’s syndrome), in which Caroli’s disease is associated with periportal fibrosis corresponding to CHF (64).The two varieties may occur in the same family, and both are associated with kidney abnormalities corresponding to ARPKD (30). Both varieties are inherited in an autosomal-recessive manner. The incidence of Caroli’s disease is much lower than that of Caroli’s syndrome.

As with CHF, some cases of Caroli’s syndrome have been reported that were associated with the adult type of polycystic disease (see below) or with a choledochal cyst (65). Variation in anatomical patterns (diffuse forms, localized forms) (66)and variations in clinical appearance (symptoms in the neonatal age, later-appearing symptoms and latent forms) have been described. In the simple variety (Caroli’s disease), the abnormality consists of moniliform or saccular dilatations of the larger IHBDs (left and right hepatic ducts, segmental ducts and some of their afferent branches), with predominant involvement of the segmental ducts (30). The dilated parts are in continuity with the rest of the biliary system and hence contain bile (communicating type of cystic disease). Some studies have indicated the presence of polypoid projections or of crossbridges in the dilated lumina (17, 39)(Fig. 3). The saccular dilatations of the ducts are a predisposing factor in stagnation of bile, and in this way are at the root of biliary sludge formation and intraductal lithiasis, which are often complicated by superinfection. In Caroli’s syndrome, the abnormalities of the larger ducts are associated with the lesions of CHF mentioned before. The duct anomalies of Caroli’s disease are a predisposing factor in repeated attacks of cholangitis, often complicatedby biliary abscess formation and septicemia. Further complications include amyloidosis and cholangiocarcinoma (67). In patients with Caroli’s syndrome, the clinical symptoms may be a combination of the symptoms of

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FIG.13. Detail of liver biopsy specimen from a patient with ADPKD.The microphotographillustratesa von Meyenburgcomplex,with atrophy and disappearance of bile duct components in a hyalinizing stroma in the right part of the picture. On the left side, the stroma is less dense and the bile duct structures are better preserved. Some appear as dilated ducts with central, epithelium-covered fibrous axes or polypoid projections (ductal plate configurations).Some lumina contain inspissated bile (H&E; original magnification x 312).

Caroli’s disease and CHF: cholangitis and portal hypertension. The pathogenesis of Caroli’s disease seems to involve total or partial arrest of remodeling of the ductal plate of the larger IHBDs (Figs. 3 and 9). Indeed, the macroscopic appearance of the dilated ducts (39) and their visualization with modern imaging techniques ( 17-20) are most consistent with a DPM pattern. In Caroli’s syndrome, the hereditary factor causing the partial or complete arrest in remodeling of the ductal plates seems to exert its influence not only during the early period of bile duct embryogenesis,but also later on during the stage of development of more peripheral biliary ramifications (the interlobular bile ducts), thus resulting in the development of the lesions of CHF in the more peripheral levels of the biliary tree. This hypothesis, already proposed by Caroli himself (30), may explain the autosomal-recessivetransmission of the disease and its association with ARPKD. Furthermore, this pathogenetic mechanism implies the same basic defect in the two conditions combined in Caroli’s syndrome; that is, DPM in different levels of the biliary tree developing in successive periods during the embryological development of the IHBDs (Caroli’s disease and CHF) (Fig. 9). DPM of IHBDs often seems to be associated with some form of involution or destruction of the immature ducts (see previous discussions of EHBDA, ARPKD and CHF). It would be of interest to investigate with modern, noninvasive imaging techniques whether Caroli’s disease (or syndrome) is associated in some cases with EHBDA. If such an association could be confirmed, it

would explain the occurrence of biliary cysts observed in some infants with EHBDA treated by portoenterostomy (22, 68). Caroli’s disease may be associated with choledochal cyst, the pathogenesis of which remains unknown but may be related to bile duct atresia (69, 70). Furthermore, the choledochal cyst types IVA and type V according to Todani are very similar to the appearance of Caroli’s disease (71). In short, the basic lesion of Caroli’s disease corresponds to DPM of the larger IHBDs, which may be associated with DPM of the more proximal and of the more distal segments of the biliary system. uon Meyenburg Complex. von Meyenburg complexes are usually described as bile duct microhamartomas (72). These small (often multiple) lesions are mostly asymptomatic incidental findings. They may occur in an otherwise normal liver or in association with Caroli’s disease and CHF. A von Meyenburg complex comprises a variable number of more-or-less dilated bile ducts embedded in a fibrous, sometimes hyalinizing stroma. The lumen may contain inspissated bile concrements. Some of the duct structures may show polypoid projections in the lumen; others show on section a central island of connective tissue covered with the same type of epithelium as that lining the wall of the dilated duct. The latter two appearances recall the basic configuration of DPM (Fig. 13). The complexes are located in or close to portal tracts. In some complexes, the bile duct profiles are involutive and disappear in a hyalinized, scarring stroma. In most cases, von Meyenburg complexes represent stationary embryonic remnants; only rarely are they the

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FIG. 14. Same liver specimen shown in Figure 13 (ADPKD).Overview of larger von Meyenburg complex; its appearance is consistent with the interpretation of multiple, partly remodeled ductal plates due to fusion of adjacent portal tracta (pollard willow branching pattern of the portal vein) (Compare with Figure 6 ) . In this lesion, the bile duds are of smd caliber, corresponding to (variably dilated) peripheral twigs of the biliary tree (HQE; original magnification x 125)

site of origin of cholangiocarcinoma (72).However, von Meyenburg complexes seem to be at the origin of the development of adult type polycystic liver disease (see below), by their progressive dilatation and fluid filling of the original clusters of bile duct structures (73,74). The morphological appearance of von Meyenburg complexes allows the following hypothesis on their morphogenesis: the lesion represents a partially fibrosing (and on occasion slowly involutive) remnant of DPM of the smaller, more peripheral branches of the intrahepatic biliary tree. This hypothesis invokes a fador arresting or perturbing the remodeling of the ductal plates in the later phases of development of the IHBDs (Fig. 9). In view of the sometimes-largenumber of duct profiles in a von Meyenburg complex, which occasionallyappears as a conglomerate of approximated ductal plate remnants,one also must take into account the abnormality in the arborization pattern of the peripheral branches of the portal vein similar to that observed in “early severe” EHBDA and in CHF; that is, the pollard willow pattern of r d c a t i o n of the portal vein, which causes close apposition and even fusion of the corresponding portal tracts (Figs. 14 and 15). The paraportal location of some von Meyenburg complexes, fused to normal-appearing portal tracts (Fig. 15), suggests that one of the branches of the “pollard willow” may give rise to a normal portal tract with normal duct development, whereas the rest of the tuft evolves into hypoplastic vein branches with fusion of adjacent portal tracts and clustering of their ductal plates.

The classic theory states that the dilated ducts of the von Meyenburg complexes do not communicate with the rest of the biliary tree, as is also the case in adult type polycystic liver disease (noncommunicating cystic disease) (38).This would hardly be compatible with a DPM origin of the lesions. However, recent investigations on a human complex (75) and studies in the CPK mouse and in the infantile and adult types of human polycystic disease have, to the contrary, indicated the communicating nature of these bile duct abnormalities (76, 77). These newer observations thus render the pathogenetic hypothesis of a DPM origin of the lesions more acceptable. Autoeomcrl Dominant Polycystic gidney Dieecure. Because the “adult type” of polycystic liver and kidney disease may also manifest itself in early childhood (781, its nomenclature has been changed to “autosomal dominant polycystic kidney disease” (ADPKD)(79). ADPKD is the most common hereditary kidney abnormality, with an incidence of 1in 500 to 1in 5,000 in the general population. Recent gene-linkage studies using a highly polymorphic DNA probe for the a-hemoglobin region on the short arm of chromosome 16 have indicated the localization of a causative gene (PKD-1) very close to the marker probe on chromosome 16. A second gene (PKD-2) may be involved in some families (80). The chromosome carrying the PKD-2 gene has not been identified. The animal model of ADPKD is the CFWwd strain of AKR mouse (81). In addition to kidney and liver cysts, ADPKD may also

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FIG.15. Same liver specimen shown in figures 13 and 14 (ADPJSD). The picture illustrates part of two larger bile duct cysts (C1, CJ. Note the presence of three von Meyenburg complexes (center of picture) in a paraportal position close to the portal tract between the larger cysts C, and C,. The von Meyenburg complexes (although dilated) correspond to small-caliber ducts (terminal ramifications of the biliary tree) (H&E; original magnification x 125).

include other malformations such as pancreatic cysts, colon diverticula, heart valve abnormalities, berry aneurysms, aneurysm of the thoracic aorta and inguinal hernia (79). Furthermore, ADPKD may be associated with Caroli’s syndrome (65) and with CHF (82). In ADPKD, liver cysts are found in most patients, but their prevalence increases with age. The size of the liver varies; it may remain unchanged for many years but increase later. Macroscopically, the liver contains multiple cysts of variable diameter disseminated throughout the organ or, more rarely, restricted to one lobe. The cysts are located in or very close to portal tracts. The cavities are lined by a cuboidal, biliary type of epithelium and surrounded by a fibrous capsule. The cysts are frequently associated with von Meyenburg complexes or with zones of fibrosis of the CHF type (82) (Fig. 15).The cysts are considered to be of the noncommunicating type (38, 82, 83). The cysts contain a clear fluid with a composition close to that of the bile saltindependent fraction of bile (84). The fluid is secreted by the lining epithelial cells. Cysts may become infected and fill with pus. The hepatic cysts in ADPKD are considered to result from progressive dilatation of the dilated ducts in von Meyenburg complexes (73). An inverse relationship was found between the number of cysts and the number of von Meyenburg complexes in one study (74), but not in another (77). As mentioned earlier, the von Meyenburg complexes can be considered to result from DPM of the peripheral interlobular bile ducts and thus caused by a factor

intervening in the later phase of bile duct embryogenesis (Fig. 9). This concept correlates with the kidney abnormality in ADPKD; the kidney cysts correspond to dilatation not only of collecting ducts, but of all segments of the nephron, including the later-formed metanephric derivatives (tubules and glomeruli). The postulated noncommunicating nature of the liver cysts in ADPKD might argue against their DPM origin. However, it is conceivable that the ductal structures of a von Meyenburg complex, originally communicating with the biliary tree, might become separated and noncommunicating as a result of their progressive dilatation and of stricture by the strangulating hyaline fibrosis that surrounds them. Furthermore, as mentioned, recent studies contradict the noncommunicating nature of the cysts in ADPKD (75). The association of ADPKD with CHF (82) and with Caroli’s syndrome (65) suggests a lack of adequate remodeling of ductal plates at all levels of the biliary tree, invoking the influence of a causative agent throughout the whole period of embryogenesis of the IHBD (Fig. 9). Because the mode of inheritance is different in ADPKD from that in ARPKD (CHF, Caroli’s disease), we must recognize the combination of at least two genetic factors in such cases: one dominant and one recessive. Similar associations have been observed in a single kindred (49). In addition to genetic factors, the development of

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liver cysts in ADPKD is further modulated by nongenetic factors such as age, pregnancy, female gender and severity of kidney lesions (85).

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8. Ruebner BH, Blankenberg TA, Burrows DA, Soohoo W, Lund JK.

Development and transformation of the ductal plate in the developing human liver. Pediatr Path01 1990;10:55-68. 9. Shah K,Gerber MA. Development of intrahepatic bile ducts in humans; immunohistochemical study Using monoclonal cgtoMESENCEYMAL HAMARTOMA keratin antibodies. Arch Path01 Lab Med 1989;113:1135-1138. Mesenchymal hamartoma is a benign, tumorlike 10. Shah KD,Gerber MA. Development of intrahepatic bile ducts in lesion that occurs almost exclusively in young children 11. humane. Arch Pathol Lab Med 1990;114:597-600. Stosiek P, Kasper M, Karsten U. Expression of cytukerath 19 (average age = 15 mo), mostly boys. The lesion appears during human liver orgamyipnesis. Liver 1990;1059-63. as a progressively enlarging tumor and is usually found 12. Van Eyken P, Sciot R, Callea F,Van der Steen K, Moerman P, Deem& VJ. The developmentof the intrahepatic bile ducts in man: in the right liver lobe (86). a keratin-immunohistochochemicalstudy. -PM’~= 1988;81586Most of the tumor consists of loose, edematous 1595. connective tissue, dilated vessels and lymphatics and 13. Van Eyken P, Sciot R, Desmet V. Intrahepatic bile duct develmultiple bile ducts (often in their early embryonic shape opment in the rat a cytokeratin-immunohistochemical study. Lab [DPM]). Islands of parenchymal cells are scattered in Inv& 1988,5952-59. 14. Moll R, Frankem,Schiller DA, Geiger B, Krepler R. The catalog between. of human qtokeratim patterns of expression in normal epithelia, The exad pathogenesis of mesenchymal hamartoma and cultured cells. Cell 1982;31:11-24. is unknown; the prevalent theory is that it represents 15. tumors D o l j d L, Roulet F. Ueber die gestaltende Wechselwirkung aberrant development of primitive mesenchyme in zwieehen dem Epithel und dem Meaenchym, zugleich ein Beitrag zur Histogenese der sogenannten ‘‘Gallengangswucherungen.” portal tracts (871, apparently associated with disturbed Virchows Arch [A] 1934;292:256-267. remodeling of ductal plates. Jtirgensen MJ. The ductal plate malformation: a study of the 16. The rapid enlargement of the tumor is thought to be intrahepatic bile-duct lesion in infantile polycystic disease and caused by cystic degeneration of the mesenchyme with congenital hepatic fibrosis. Acta Path01 Mimbiol Scand Suppl secondary fluid accumulation in cysts, obstruction and 1977;257. dilatation of lymphatics or both (86, 88). Treatment 17. Marchal GJ,Desmet VJ, ProasmansWC, Moerman PL, Van Roost WW,Van Holsbeeck MT, Baert AL. Caroli diesaee:high frequency consist8 of excision; recurrence or malignant transforUS and pathologic findings. Radiology 1986,158507-511. mation does not follow (88). 18. Sood GK, Mahapatra JR, Khurana A, Chaudluy U, Sarin SK, Very rare cases of mesenchymal hamartoma have Bmor SK. Caroli disease computed tomographic diagnosis. been reported in adults (89). Gastrointeet Radio1 1991;16243-244. 19. Huseman KL, F’riedwald JP, Gollub MJ, M h e d J. Cadi’s CONCLUSION disease associated with infantile polycystic kidney disease. J ultrasound Med 1991;10235-237. In conclusion, this review emphasizes that DPM is a 20. Hopper KD. The role of computed tomography in the evaluation basic morphologicallesion that occurs at different levels of Cmli’s disease. Clin Imaging 1989;136&73. of the biliary tree in the various types of congenital bile 21. Desmet VJ. Intrahepatic bile ducts under the lens. J Hepatol 1985;1:M-559. duct disease. It is hoped that this view will have a h m e t VJ, Callea F. Cholestatic syndromes of infancy and positive and stimulating effect on thinking and on 22. childhood. In: Zakim D, Boyer TD,eds. Hepatology: a textbook of investigation of these various conditions. liver disease. Vol 2. 2nd ed. Philadelphia: W.B.Saundem Co., 1990:1355-1395. 23. Desmet VJ. Etiologie, auatomo-pathologie,6volution des lhions REFERENCES d’origine gbn6tique de l’arbre biliaire. In: Encyclop6die m6dico1. Desmet VJ. Cholangiopathies: past, present and future. Semin chirurgicale. P a r k Editions Techniques, 1992. Liver Die 1987;767-76. 24. Raweily EA,Gibson AAM,Burt AD. Abnormalities ofintrahepatic 2. Deamet VJ. Embryology of the liver and intrahepatic biliary tract, bile ducts in extrahepatic biliary atresia. Hietopathology 1990;17: and an overview of malformationsof the bile duct. In: McIntyre N, 521-527. Benhamou J-P, Bircher J , Rizzetto M,Rod& J , eds. The Oxford 25. h m e t V. What is congenital hepatic fibrosis? Histopathology textbook of clinical hepatology. Vol 1. Oxford Oxford University 1992;20:465-477. Press,1991:497-519. 26. Laurent J, Gauthier F, Bernard 0, Hadchouel M, OdieMe M, 3. Hammar JA. Uber die erste Entstehung der nicht kpillaren Vdayer M,AlagiUe D. Long-term outcome after surgery for biliary intrahepatiachen Gallengibe beim Menschen. 2 Mikrosk Anat atresia: study of 40 patients surviving more than 10 years. Forsch 1926559-89. Gastroenterology 1990;99:1793-1797. 4. Blankenberg TA, Lund JK,Reubner BH. Normal and abnormal 27. C a l l a F, Facchetti F, Lucini L, Favret M, Zorzi F, Guerini A, development of human intrahepatic bile ducts: an immunohisBonetti M, et al. Liver morphology in ani&c patients at tochemical perspective. In: Abramowsky CR, Bemetein J, long-term follow-up after Kasai operation: a study of 16 cnaes. In: RosenbergHS,eds.Perspectives in pediatricpathology: transplanOhi R, ed. Biliary atresia. Tokyo: Profeeaional Postgraduate tation pathology-hepatic morphogenesis. Basel: Karger, 1991: Services, 1987:304-310. 143-167. 28. Kahn E. Paucity of interlobular bile ducts: arteriohepatic dys5. Burt AD, Stewart JA, Aitchison M,MacSween RNM. Expression plesia and nonsyndromic duct paucity. In: Abramowaky CR, of tiseue polypeptide antigen (TPA) in fetal and adult liver: Bernetein J, Rosenberg HS, eds. Perspectives in pectiatrc pachanges in liver dieeaae. J Clin Pathol1987;40:719-724. thology: transplantation pathology-hepatic morphogeneais. 6. Deernet VJ, Van Eyken P, Sciot R. cytokeratins for probing cell Baeel: Karger, 1991:168-215. lineage relationships in developing liver. H E p m m 1990;12: 29. Riely CA. Familial intrahepatic cholestatic syndromes. Semin 1249-1251. LimDie 1987;7:119-133. 7. Gall JAM, Bathal PS. Liver and biliary: morphological and 30. C a d i J, Come V. Maladies des voies biliairee intrah6patiques segmentaires. Paris: Maseon et Cie, 196459-154. immunohistochemicalassessment of intraheDatic bile duct development in the rat. J Gastroenterol Hepatol i989;4:241-250. 31. Welling LW,Grantham JJ. Cystic diseases of the kidney. In:

1082

DESMET

Tisher CC, Brenner BM, eds. Renal pathology with clinical and functional correlations. Philadelphia: J.B. Lippincott Co., 1989: 1233-1275. 32. Buts JP, Otte JB,Claus D, Van Craynest MP, Demeyer R. Kyste du chol6doque: un cas avec dilatation des voies biliaires intrah6patiques et fibrose h6patique congbitale. Helv Paediatr Ada 1980;35:289-295. 33. Henry X, Marrasse E, Stoppa R, Capron JP, Sevestre H. Association maladie de Caroli- kyste du chol6doque-fibrose hhpatique coenitale- polykystose rhnale. Chirurgie 1987;113: 834-843. 34. Cole BR. Autosomal recessive polycystic kidney disease. In: Gardner KD Jr, Bernstein J, eds. The cystic kidney. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1990:327-350. 35. Reeders ST. The genetics of renal cystic disease. In: Gardner KD Jr, Bernstein J, eds. The cystic kidney. Dordrecht, The Netherl a n h Kluwer Academic Publishers, 1990:117-146. 36. Avner ED, McAteer JA, Evan AP. Models of cysts and cystic kidneys. In: Gardner KD Jr, Bernstein J, eds. The cystic kidney. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1990: 55-98. 37. Blyth H, Ockenden BG. Polycystic disease of kidneys and liver presenting in childhood. J Med Genet 1971;8:257-284. 38. Witzleben CL. Cystic diseasesof the liver. In: Zakim D, Boyer TD, eds. Hepatology: a textbook of liver disease. Vol 2. 2nd ed. Philadelphia: W.B. Saunders Co., 1990:1395-1411. 39. Nakanuma Y, Terada T, Ohta G, Kurachi M, Matsubora F. Caroli’s disease in congenital hepatic fibrosis and infantile polycystic disease. Liver 1982;2:346-354. 40. Osathanondh V, Potter EL. Pathogenesis of polycystic kidneys. Arch Path01 1964;77:466-473. ~ Brennan LP, Fine 41. Lieberman E, Salinas-Madrigal L, G w i JL, RN, Landing BH. Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine 1971;50: 277-318. 42. Bernstein J, Stickler GB, Nee1 IV. Congenital hepatic fibrosis: evolving morphology. APMIS Suppl 1988;4:17-26. 43. Premkumar A, Berdon WE, Levy J, Amodio J, Abramson SJ, Newhouse JH.The emergence of hepatic fibrosis and portal hypertension in infants and children with autosomal recessive polycystic kidney disease: initial and follow-up sonographic and radiographic findings. Pediatr Radio1 1988;18:123-129. 44. Gang D, Henin J. Infantile polycystic disease of the liver and kidneys. Clin Nephrol 1986;25:28-36. 45. Kerr DNS, Harrison CV,Sherlock S, Milnes Walker R. Congenital hepatic fibrosis. Q J Med 1961;30:91-117. 46. Alvarez F, Bernard 0,Brunelle F, HachavelM, Leblanc A, Odibvre M, Alagille D. Congenital hepatic fibrosis in children. J Pediatr 1981;99:370-375. 47. Landing BH, Wells TR, Claireaux AE. Morphometric analysis of liver lesions in cystic diseases of childhood. Hum Pathol (~~pp1)1980;11:549-560. 48. Blankenberg TA, Ruebner BH, Ellis WG, Bernstein J, Dimmick JE. Pathology of renal and hepatic anomalies in Meckel’s syndrome. Am J Med Genet Suppl 1987;3:395-410. 49. Matsuda 0,Ideura T,Shin& T, Shiigai T, Takeuchi H, Wei-Chia C, Miyake S. Polycystic kidney of autosomal dominant inheritance, polycystic liver and congenital hepatic fibrosis in a single kindred.Am J Nephrol 1990;10:237-241. 50. Tazelaar HD, Payne JA, Patel S.Congenital hepatic fibrosis and asymptomatic familial adult-type polycystic disease in a 19year-old woman. Gastroenterology 1984;86 757-760. 51. Proesmans W, Moerman P, De Praetere M, Van Damme B. Association of bilateral renal dysplasia and congenital hepatic fibrosis. Int J Pediatx Nephrol 1986;7:113-116. 52. Witzleben CL, Sharp A. “Nephronophthisis-congenital hepatic fibrosis”: an additional hepatorenal disorder. Hum Patholl982; 13:728-733. 53. Clermont RJ, Maillard J-N, Benhamou J-P, Fauvert R. Fibrose hhpatique conghitale. Can Med Assoc J 1967;97:1272-1278. 54. Summerfield JA, Nagefuchi Y,Sherlock S, Cadafalch J, Scheuer

HEPATOLQGY

PJ. Hepatobihy fibropolycystic disease: a clinical and histological review of 51 patients. J Hepatol 1986;2:141-156. 55. Murray-Lyon IM, Ockenden BG, Williams R. Congenital hepatic fibrosis: is it a single clinical entity? Gastroenterology 1973;64: 653-656. 56. Potet F, Molas G, Feldmann G, Barge J. Problemes anatomocliniques pods par la fibrose hhpatique coenitale. Cah Med (Europa Medica) 1971;12:1015-1030. 57. Hausner RJ, Alexander RW. Localized congenital hepatic fibrosis presenting as an abdominal mass. Hum Path01 1978;9:473-476. 58. Phillips MJ, Poucell S, Patterson J, Valencia P. The normal liver. In: Phillips MJ, Poucell S, Patterson J, Valencia P, eds. The liver: an atlas and text of ultrastructural pathology. New York Raven Press, 19871-35. 59. Parker RGF. Fibrosis of the liver as a congenital anomaly. J Path01 Bacterial 1956;71:359-368. 60. A h CM, Danks DM, Campbell PE. Comments upon the classification of infantile polycystic diseases of the liver and kidney, based upon three-dimensional reconstruction of the liver. J Med Genet 1974;11:234-243. 61. Bernstein J, Gardner KD Jr. Renal cystic disease and renal dysplasia. In: Walsh PC, Gittes RF, Perlmutter AD, Stamey TA, eds. Campbell’s urology. 5th ed. Philadelphia: W.B. Saunders Co., 1986:1760-1803. 62. Harris HW, Carpenter TO, Shanley P, &sen S, k e y RH, Harmon WE. Progressive tubulointerstitial renal disease in infancy with associated hepatic abnormalities. Am J Med 1986; 81~169-176. 63. Cohen AH, Hoyer JR. Nephronophthisis: a primary tubular basement membrane defect. Lab Invest 1986;55:564-572. 64. Mall JC, Chahremani GG, Boyer JL. Caroli’s disease associated with congenital hepatic fibrosis and renal tubular ectasia.Gastroenterology 1974;66:1029-1053. 65. Jordan D, Harpaz N, Thung SN. Caroli’s disease and adult polycystic kidney disease: a rarely recognized association. Liver 19899:30-35. 66. Guntz P, Coppo B, Lorimier G, Cronier P, Guntz M. La maladie de Caroli unilobaire. J Chir (Park) 1991;128:167-181. 67. Fozard JB, Wyatt JI, Hall RI. Epithelial dysplasia in Caroli’s disease. Gut 1989;30:1150-1153. 68. Fain JS, Lewin KJ. Intrahepatic biliary cysts in congenital biliary atresia. Arch Path01 Lab Med 1989;113:1383-1386. 69. Landing BH. Considerations on the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst the concept of infantile obstructive cholangiopathy. Prog Pediatr Surg 1974;6: 113-139. 70. Ryckman FC, Noseworthy J. Neonatal cholestatic conditions requiring surgical reconstruction. Semin Liver Dis 1987;7: 134-154. 71. Todani T, Watanabe Y, Narusue M, Tabuchi K, Okajima K. Congenitalbile duct cysts: classification,operative procedures and review of thirty-seven cases, including cancer arising from choledochal cyst. Am J Surg 1977;134:263-269. 72. Burns C, Kuhns JG, Wieman TJ. Cholangiocarcinomain association with multiple biliary microhamartomas. Arch Path01 Lab Med 1990;1141287-1289. 73. Melnick PJ. Polycystic liver: analysis of seventy cases. Arch Path01 1955;59:162-172. 74. Karhunen PJ. Adult polycystic liver disease and biliary microhamartomas Won Meyenburg‘s complexes). Acta Path01Microbiol Immunol Scand [A] 1986;94:397-400. 75. Ohta W, Ushio H. Histological reconstruction of von Meyenburg‘s complex on the liver surface. Endoscopy 1984;16:71-74. 76. Grimm PC, Crocker JF, Malatjalian DA, Ogborn MR. The microanatomy of the intrahepatic bile duct in polycystic diseaee. comparison of the cpk mouse and human. J Exp Path01 1990;71: 119-131. 77. Ramos A, Torres VS, Holley KE, Offord Kp, Rakela J, Ludwig J. The liver in a u t o s o d dominant polycystic kidney diseaee: implications for pathogenesis. Arch Pathol Lab Med 1990;114: 180-184. 78. Milutinovic J, Schabel SI, Ainsworth SK. A u t o s o d dominant

Vol. 16, No. 4, 1992

79.

80.

81.

82. 83.

CONGENITAL DISEASES OF INTRAHEPATIC BILE DUCTS

polycystic kidney disease with liver and pancreatic involvement in early childhood. Am J Kidney Dis 1989;13:340-344. Gabow PA. Autommal dominant polycystic kidney disease. In: Gardner KD Jr, Bematein J , eds. The cystic kidney. Dordrecht, The Netherlands: Kluwer Academic Publishers, 1990;296326. Kimberling WJ, Fain PR, Kenyon JB, Goldgar D, Sujansky E, Gabow PA. Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J M d 1988;319:913-919. Werder AA, A m o s MA, Nielaen AH, Wolfe GH. Comparative effeds of germ-free and ambient environment on the development of cystic kidney disease in CFW wd mice. J Lab Clin Med 1984,103:399-407. Grunfeld J-P, Albouze G, Junger P. Liver changes and complications in adult polycystic kidney disease. Adv Nephrol 1986; 14:l. Piccoli DA, Witzleben CL. Disorders of the intrahepatic bile ducts. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB,ede. Pediatric gastrointestinal disease: pathophysiology, diagnosis, management. Philadelphia: B.C. Decker, Inc, 1991:1124-1140.

1083

M, Gonzalez-Vitale JC, Fagan CJ. Polycystic liverdisease: a study of cyst fluid constituents. HEPATOLOGY 1982;2: 476-478. 86. Gabow PA, Johnson AM, Kaehny WD,MancoJohnson ML,Duley IT, Evereon GT. Risk fadore for the development of hepatic cyata in a u t o s o d dominant polycystic kidney disease. HEPATOLOGY 1990;11:1033-1037. 86. Stocker JT,Ishak KG. Mesenchymal hamartoma of the liver: report of 30 cases and review of the literature. Pediatr Path01 1983;1245-267. 87. Dehner LP, Ewing SL, Summer HW. Infantile mesenchymal hamartoma of the liver: histologic and ultrastructural observations. Arch Path01 1975;99:379-381. 88. De Maioribus CA, Lally KP, Sim K, Isaaca H, Mahour GH. Mesenchymal hamartoma of the liver: a 36-year review. Arch Surg 1990;125:598-600. 89. Drachenberg CB, Papadimitriou JC, River0 MA, Wood C. Adult mesenchymal hamartoma of the liver: report of a case with light microscopic, FNA cytology, immunohietoehemietrg, and ultrastructural studies and review of the literature. Mod Pathol 1991;4:392-395. 84. Pattenson