Ultrasound Visualization of Hepatic Peribiliary Cysts: A Comparison with Morphology

We report herein a hitherto unrecognized, interesting ultrasound finding ("hilar multicystic echo complex"), the result of peribiliary cysts in the liver. This ultrasound finding was discovered around intrahepatic large bile ducts and large portal vein branches near the hepatic hilum in an autopsy case with hepatocellular carcinoma, submassive hepatic necrosis superimposed on chronic active hepatitis, and portal hypertension. Antemortem ultrasound examination revealed the hilar multicystic echo complex around the portal venous branches near the hepatic hilum. Autopsy confirmed that the hilar multicystic echo complex was due to peribiliary cysts that were present around the bile ducts at the hilum. The peribiliary cysts were thought to have arisen from cystic dilatation of preexisting intrahepatic peribiliary glands. These peribiliary cysts reportedly occur in livers with portal hypertension (e.g., cirrhosis, hepatocellular carcinoma, idiopathic portal hypertension, extrahepatic portal obstruction, and portal thromboembolism), adult-type polycystic disease of the liver and kidneys, and systemic infection. Therefore, recognition of peribiliary cysts at sonography would have diagnostic value, and may indicate that presence of one of the above described liver diseases.     

Intrahepatic peribiliary glands of humans. II. Pathological spectrum

Abstract The pathological spectrum of intrahepatic peribiliary glands is reviewed here. Several categories of histopathological changes such as necro-inflammation, cystic dilatation, hyperplasia and neoplasia have been identified in this glandular system. Necro-inflammation is associated with biliary tract diseases and chronic advanced liver diseases and may also appear in the livers of subjects with extrahepatic diseases such as sepsis. Cystic changes of microscopic sizes are not uncommon in autopsy livers of chronic advanced liver diseases, portal hypertensive diseases and also polycystic liver of adult type. Grossly recognizable cysts are, however, infrequent and occasionally cause compression of the adjoining bile ducts. Hyperplasia of these glands, which occurs consistently in hepatolithiasis and more variably in other conditions (e.g. biliary tract infection and submassive hepatic necrosis), may be associated with hypersecretion of seromucinous substances. Hyperplasia of peribiliary glands may then lead to mucin-related biliary diseases. In addition, these glands, particularly the hyperplastic ones, could be a precursor of cholangiocarcinoma. The pathological spectrum of the intrahepatic peribiliary glands is being expanded, although a clinical pathological correlation remains uncharted. Furthermore, age-related variations and non-specific reactive changes of these glands remain unexplored.     

Innervation of intrahepatic bile ducts and peribiliary glands in normal human livers, extrahepatic biliary obstruction and hepatolithiasis. An immunohistochemical study

Innervation of the intrahepatic biliary tree was examined in human normal livers, extrahepatic biliary obstruction and hepatolithiasis. Nerve fibers were immunohistochemically identified on formalin-fixed and paraffin-embedded sections by antibodies to S-100 protein (S-100) and neuron specific enolase (NSE). S-100 and NSE-immunoreactive nerve fibers were present in the walls of intrahepatic large, medium-sized and septal bile ducts as well as in peribiliary glands. Some nerve fibers were in close contact with epithelia of bile ducts and peribiliary glands. Serial section observations showed that the nerve fibers arising from nerve bundles approached, and came to lie in close contact with epithelia of the bile ducts and peribiliary glands. Nerve fibers were sparse around the interlobular bile ducts and bile ductules. These immunoreactive nerve fibers of the intrahepatic biliary tree were rather sparse in normal livers, intermediate in extrahepatic biliary obstruction and dense in hepatolithiasis. These findings suggest that intrahepatic bile ducts and peribiliary glands are innervated and biliary functions are regulated in part by these nerve fibers. Increased nerve fibers may have altered effects on biliary functions in hepatolithiasis.     

Association of Carcinoma with Congenital Cystic Conditions of the Liver and Bile Ducts

Reported cases of carcinoma arising in association with congenital cystic conditions of the liver and bile ducts are tabulated with respect to the specific type of congenital abnormality. The occurrence of carcinoma in solitary nonparasitic cysts of the liver or as a complication of polycystic liver disease is distinctly rare. Carcinoma will arise with a frequency of approximately 1% in congenital hepatic fibrosis, 4% in choledochal cyst and 7% in congenital cystic dilatation of the intrahepatic bile ducts. Those congenital conditions exposing the epithelium to the bile directly are at greater risk for the development of malignancy. Carcinoma in this clinical setting occurs several decades earlier than otherwise expected.     

Immunohistochemical demonstration of pancreatic alpha-amylase and trypsin in intrahepatic bile ducts and peribiliary glands

Epithelia of intrahepatic bile ducts and peribiliary glands were immunohistochemically examined for pancreatic alpha-amylase and trypsin in 54 normal autopsied livers. alpha-Amylase was evaluated with a polyclonal antibody, and trypsin was assayed with both polyclonal and monoclonal antibodies. alpha-Amylase was observed in large ducts, septal ducts and peribiliary glands in most livers and was seen in interlobular ducts in seven (13%) livers. Trypsin immunoreactivity with the polyclonal antibody was observed in peribiliary glands in 21 (39%) livers; it was absent in intrahepatic bile ducts in all but one liver. Trypsin immunoreactivity with the monoclonal antibody was present in large ducts, septal ducts and peribiliary glands in about 70% of the livers and was seen in interlobular ducts in two (4%) livers. Bile ductules were always negative for the two antigens. Some epithelia of peribiliary glands positive for both alpha-amylase and trypsin histologically resembled pancreatic acinar cells. alpha-Amylase and trypsin immunoreactivities of intrahepatic biliary epithelia and pancreatic aninar cells were eliminated by absorption of primary antibodies by alpha-amylase or trypsin, suggesting the specificities of the immunoreactivities. These data suggest that epithelia of intrahepatic large ducts, septal ducts and peribiliary glands contain pancreatic alpha-amylase in most livers and that they contain trypsin in about 70% of livers. alpha-Amylase and trypsin may be secreted into intrahepatic bile duct lumens, thereby exerting important effects on the physiology of the intrahepatic biliary tree and hepatic bile.     

Multiple hilar cysts of the liver in patients with alcoholic cirrhosis: Report of three cases

The present report concerns the clinicopathological study of three patients with alcoholic cirrhosis (a 40-year-old man, a 52-year-old woman and a 48-year-old man) who had multiple cysts along their intrahepatic bile ducts. The cysts were visible on gross examination of the liver and, in two cases, an enlargement of the cysts had been detected in abdominal computed tomography scans performed 1 year apart. Histologically, the cysts consisted of proliferating and dilated peribiliary glands. The cysts occasionally compressed the original bile ducts. The latter showed mucosal hyperplasia with antral-type gland metaplasia. Neoplastic changes and necroinflammation were not seen. Immuno-histochemical assays revealed that the peribiliary glands and antral-type glands expressed not only cytokeratin and carbohydrate antigen 19-9, but also c-MET protein, the hepatocyte growth factor receptor which may be related, at least in part, to the cystic dilatation of the peribiliary glands.     

Vascular plexus around intrahepatic bile ducts in normal livers and portal hypertension

Vessels around the intrahepatic large bile ducts (peribiliary vascular plexus) were examined by histologic, immunohistochemical and scanning electron microscopic observations. The vessels within duct walls were mainly capillaries, while those around the duct walls were composed of capillaries and venules. A majority of vessels was positive for factor VIII-related antigen and Ulex europaeus lectin I. Scanning electron microscopy of hepatic arterial and biliary casts revealed that bile ducts were surrounded by the vascular plexus derived from hepatic arterial branches, and serial section observations in addition disclosed the vessels connecting the peribiliary plexus with portal venous branches ('internal roots'). The peribiliary vascular plexus was increased considerably in livers with portal hypertension, especially idiopathic portal hypertension, extrahepatic portal venous obstruction and hepatocellular carcinoma with portal venous tumor thrombi. Internal roots were also frequently found in the livers with portal hypertension. These results suggest that altered intrahepatic hemodynamics in portal hypertensive conditions involves the peribiliary vascular plexus, resulting in an increase of the number and frequent occurrence of 'internal roots', these vessels probably operating as intrahepatic collaterals.     

Ultrastructural and immunohistochemical studies of the intrahepatic peribiliary capillary plexus in normal livers and extrahepatic biliary obstruction in human beings.

Ultrastructural and immunohistochemical study was conducted on the intrahepatic peribiliary capillary plexus in normal livers and in those with extrahepatic biliary obstruction. In both conditions, capillaries positive for Ulex europaeus agglutinin I and type IV collagen were always present in the vicinity of the bile ducts. Immunoelectron microscopy showed the presence of type IV collagen on the basal lamina of these capillaries; Ulex europaeus agglutinin I was also positive on their cytoplasms. Under electron microscope, a considerable number of these capillaries were seen as being composed of fenestrated endothelium with a diaphragm and with extreme cytoplasmic attenuations that were dense at the sides facing the bile duct in comparison with the opposite sides in normal livers. In extrahepatic biliary obstruction, plasmalemmal pinocytic vesicles, multivesicular bodies and other cellular organellae such as rough endoplasmic reticulum and Weibel-Palade bodies increased in number in these capillaries, relative to normal livers, probably reflecting increased permeability and functional activities. These characteristic ultrastructural features of the peribiliary capillary plexus might be arranged to transport substances effectively by way of intrahepatic biliary epithelial cells in normal livers and also might be altered to meet the increased functional demands of extrahepatic biliary obstruction.     

Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma

BACKGROUND/AIM: The protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. METHODS: Immunohistochemistry and a semiquantitative scoring method in normal liver and biliary diseases were used for the investigation. RESULTS: In "normal" adult livers (n=10), intrahepatic bile ducts were negative for PKR. In normal fetal livers (n=25), primitive biliary epithelia were almost negative for PKR. In primary biliary cirrhosis (PBC) (n=30), damaged bile ducts were frequently positive for PKR, while uninvolved bile ducts were negative. In hepatolithiasis (n=27), proliferated bile ducts were positive for PKR, and the PKR score correlated with the degree of proliferation. In cholangiocarcinoma (CC) (n=44), PKR expression was frequently noted, and the PKR score correlated with good differentiation of CC, being highest in well-differentiated CC and lowest in poorly-differentiated CC. The PKR score decreased in the following order: CC (mean PKR score=3.96), hepatolithiasis (2.56), PBC (1.60), normal fetal liver (0.40), and normal adult livers (0.00). The PKR expression in hepatocytes was "baseline" in normal adult livers, while moderately increased in fetal livers, PBC, hepatolithiasis and CC. CONCLUSIONS: Although the significance of these data is unclear, they suggest (i) that PKR is absent in bile ducts in normal adult and fetal livers, (ii) that PKR in bile duct cells newly emerges or increases in PBC, hepatolithiasis, and CC, (iii) that PKR accumulates in damaged bile ducts in PBC, (iv) that PKR increases in parallel with biliary cell proliferation in hepatolithiasis, and (v) that PKR expression correlates with differentiation in CC. PKR expression in intrahepatic bile ducts seems to be associated with inflammation or cell proliferation of the bile duct cells.     

Lactoferrin and lysozyme in the intrahepatic bile duct of normal livers and hepatolithiasis. An immunohistochemical study.

Lactoferrin and lysozyme have bactericidal activities and are responsible for mucosal defense against local bacterial infections. To assess the local defense mechanisms in the intrahepatic biliary tree, we studied the distribution of lactoferrin and lysozyme immunohistochemically in 14 normal autopsy livers and in 29 surgically resected and two autopsy livers of hepatolithiasis. In the latter, bacterial infection was constantly found. Lactoferrin and lysozyme were detected in low doses and in specific areas in the intramural and extramural glands of certain normal livers. In contrast, in hepatolithiasis, the incidence of lactoferrin- and lysozyme-positive cases significantly increased both in the intramural glands (94% and 77% of 31 cases, respectively) and in the extramural glands (72% and 48% of 29 cases, respectively) (p less than 0.01) in the stone-containing bile ducts. These glands proliferated considerably in the stone-containing bile ducts and were stained more widely and intensely than in normal livers. These data suggest that these proliferated peribiliary glands in the stone-containing bile ducts produce and secrete significant amounts of lactoferrin and lysozyme. Increased production and secretion of lactoferrin and lysozyme suggests activated local defense mechanisms against bacterial infection in the stone-containing bile ducts, and may be beneficial for inhibition of the growth of calculi and prevention of the suppurative inflammation.     

Glandular elements around the intrahepatic bile ducts in man; their morphology and distribution in normal livers

The morphology and distribution of the glandular elements around the intrahepatic bile ducts, hitherto poorly described, were examined in autopsied human livers with the aid of postmortem cholangiographs. The glands could be divided into intramural and extramural. The former were small in number, scattered within the bile duct walls, and were simple tubular mucous glands. The latter were more abundant, located in the periductal connective tissue, and were branched tubuloalveolar seromucous glands. Serial section observations revealed that neither gland communicated with the hepatic parenchyma, and the extramural glands drained into the large bile duct lumina via the conduits. The mucous cells of both glands contained neutral, carboxylated and sulfated glycoproteins. The extramural glands were distributed from the hepatic to the segment ducts in almost all livers, and were also discerned around the area ducts in two-fifths of the livers. The glands seemed to decrease in number as the bile ducts became more branched.     

Multiple hepatic peribiliary cysts with cirrhosis

Multiple hepatic peribiliary cysts were found in three autopsy cases of patients who had had underlying liver diseases and obstructive jaundice. Macroscopically, the cysts were visible and present exclusively in the hepatic hilum and larger portal tracts. Histologically, the cysts were of varying size and were lined by a single layer of cuboidal or flattened epithelial cells without atypia. Intimate association between the cysts and peribiliary glands was found in the walls of large bile ducts. All three cases were associated with liver cirrhosis in patients with portal hypertension, and two of the patients had also had hepatocellular carcinoma. These findings support the previous assumption that multiple hepatic peribiliary cysts may be closely related to a portal hypertensive condition. Although peribiliary cysts have been considered to be clinically asymptomatic in general, in one of our patients, the cystic dilatation appeared to have been responsible for the progression of obstructive jaundice.     

Solitary Cystic Dilation of the Intrahepatic Bile Duct: Morphology of Two Autopsy Cases and a Review of the Literature

Solitary cystic dilation of intrahepatic bile ducts with neither extrahepatic biliary anomalies nor renal lesions has been reported previously in only 11 cases. We report two cases which were found as a result of postmortem cholangiography of 149 livers at autopsy. Case 1 had a cystic dilation measuring 1.2 cm in diameter in the left lateral superior area duct. Case 2 showed a cystic dilation measuring 1.0 cm in diameter in the left lateral segment duct. Histologically, the walls of the dilated ducts consisted of fibrous wall with proliferation of periductal mucous glands in both cases. The dilated and adjacent bile ducts in case 2 also contained tiny brown pigment stones and biliary sludge, suggesting that this bile duct lesion is important in the formation of intrahepatic calculi by providing a site for bile stasis and mucous hypersecretion.     

Protein expression of double‐stranded RNA‐activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers,fetal livers,primary biliary cirrhosis,hepatolithiasis and intrahepatic cholangiocarcinoma

Abstract: Background/Aim: The protein expression of double‐stranded RNA‐activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. Methods: Immunohistochemistry and a semiquantitative scoring method in normal liver and biliary diseases were used for the investigation. Results: In “normal” adult livers (n=10), intrahepatic bile ducts were negative for PKR. In normal fetal livers (n=25), primitive biliary epithelia were almost negative for PKR. In primary biliary cirrhosis (PBC) (n=30), damaged bile ducts were frequently positive for PKR, while uninvolved bile ducts were negative. In hepatolithiasis (n=27), proliferated bile ducts were positive for PKR, and the PKR score correlated with the degree of proliferation. In cholangiocarcinoma (CC) (n=44), PKR expression was frequently noted, and the PKR score correlated with good differentiation of CC, being highest in well‐differentiated CC and lowest in poorly‐differentiated CC. The PKR score decreased in the following order: CC (mean PKR score=3.96), hepatolithiasis (2.56), PBC (1.60), normal fetal liver (0.40), and normal adult livers (0.00). The PKR expression in hepatocytes was “baseline” in normal adult livers, while moderately increased in fetal livers, PBC, hepatolithiasis and CC. Conclusions: Although the significance of these data is unclear, they suggest (i) that PKR is absent in bile ducts in normal adult and fetal livers, (ii) that PKR in bile duct cells newly emerges or increases in PBC, hepatolithiasis, and CC, (iii) that PKR accumulates in damaged bile ducts in PBC, (iv) that PKR increases in parallel with biliary cell proliferation in hepatolithiasis, and (v) that PKR expression correlates with differentiation in CC. PKR expression in intrahepatic bile ducts seems to be associated with inflammation or cell proliferation of the bile duct cells.     

Congenital cystic diseases of the intra and extrahepatic bile ducts

Congenital cystic lesions of bile ducts may affect intra or extrahepatic bile ducts. Intrahepatic lesions include five entities: congenital hepatic fibrosis, Caroli's syndrome, von Meyenburg complexes, simple cyst of the liver and polycystic liver disease. Congenital hepatic fibrosis and von Meyenburg complexes are secondary to ductal plate malformation affecting the smallest intrahepatic bile ducts. Cystic dilatations are of small size and only detected at histological examination of the liver. They have few clinical consequences. In congenital hepatic fibrosis, the main manifestations result from portal hypertension. Caroli's syndrome is secondary to ductal plate malformation affecting the largest intrahepatic bile ducts. Cystic dilatations are macroscopic and responsible for cholangitis and may lead to biliary stones and carcinoma which develop within cystic dilatations. Caroli's syndrome may be or not associated with congenital hepatic fibrosis. In case of associated congenital hepatic fibrosis, portal hypertension is present. Simple cyst of the liver and polycystic liver disease are characterized by cystic dilatations which, by contrast to the preceding entities, do not communicate with the rest of biliary tree. As a result, they have only few clinical consequences. In congenital hepatic fibrosis and polycystic liver disease, renal abnormalities are frequently observed. They correspond to renal malformations associated with biliary malformations. In congenital hepatic fibrosis, renal lesions are characterized by ectatic collecting tubules which are present in two thirds of the cases and transmitted as an autosomal recessive trait. In polycystic liver disease, renal lesions are characterized by polycystic disease which is present in half of the cases and transmitted as an autosomal dominant trait. Congenital cystic lesions of extrahepatic bile ducts consist of choledochal cyst, which is secondary to malformation of the pancreato-biliary ductal junction. The major risk of choledochal cyst is the development of intracystic cancer, the prevention of which is total surgical resection of the cyst.     

The biliary tree--a reservoir of multipotent stem cells

The biliary tree is composed of intrahepatic and extrahepatic bile ducts, lined by mature epithelial cells called cholangiocytes, and contains peribiliary glands deep within the duct walls. Branch points, such as the cystic duct, perihilar and periampullar regions, contain high numbers of these glands. Peribiliary glands contain multipotent stem cells, which self-replicate and can differentiate into hepatocytes, cholangiocytes or pancreatic islets, depending on the microenvironment. Similar cells-presumably committed progenitor cells-are found in the gallbladder (which lacks peribiliary glands). The stem and progenitor cell characteristics indicate a common embryological origin for the liver, biliary tree and pancreas, which has implications for regenerative medicine as well as the pathophysiology and oncogenesis of midgut organs. This Perspectives article describes a hypothetical model of cell lineages starting in the duodenum and extending to the liver and pancreas, and thought to contribute to ongoing organogenesis throughout life.     

Expression of blood group-related antigens in the intrahepatic biliary tree and hepatocytes in normal livers and various hepatobiliary diseases

The distribution of blood group-related antigens (A, B, H, Lea and Leb) in the intrahepatic biliary tree and hepatocytes was studied by immunoperoxidase techniques. In normal livers, large and septal bile ducts expressed A and B antigens in the cases with comparable blood groups and also expressed H antigen frequently in the cases with blood group O, A or B, and infrequently in the cases with AB. Lea and Leb were found in biliary cells at any level in secretors. In hepatobiliary diseases, A, B and H were neoexpressed in the interlobular bile ducts in addition to their expression in the large and septal bile ducts. Lea and Leb were found in almost all proliferated bile ductules and in some hepatocytes, especially those adjacent to ductules, in any of the hepatobiliary diseases, and their expression seemed parallel to the disease activity. H antigen was also neoexpressed in some hepatocytes and proliferated bile ductules. Extramural peribiliary glands expressed H, Lea, Leb and, to a lesser degree, A and B antigens in normal and pathologic conditions. This study disclosed that the normal biliary tree has a specific expression of blood group antigens at different levels and that this expression is altered in pathologic conditions. Periportal hepatocytes showed neoexpression of blood group antigens in pathologic conditions, and some of these hepatocytes may undergo ductular metaplasia.     

Interactions between epithelial and mesenchymal cells in intrahepatic peribiliary glands in normal and hepatolithiatic livers

The anatomy and pathology of the intrahepatic peribiliary glands were evaluated. In this study, we ultrastructuraly examined the peribiliary glands of normal and hepatolithiatic livers using common and serial ultrathin section observations. It is well known that these glands proliferate markedly in hepatolithiasis. These glands were composed of several acini surrounded by thickened and multilayered basement membranes, and there were mesenchymal cells (the majority were fibroblasts) in the periacinar fibrous connective tissue. Some cytoplasmic processes of acinar epithelial cells and mesenchymal cells in the periacinar connective tissue were in close contact with each other within the thickened and multilayered basement membranes. Such cell-to-cell interaction was most frequent in cases of hepatolithiasis, in which peribiliary glands proliferated markedly. In hepatolithiatic livers, some unmyelinated nerve fibers or axonal button profiles were in close contact with periacinar mesenchymal cells and also with cytoplasmic processes of glandular epithelial cells. Such contacts were rare in normal livers. These findings suggest that such epithelial and mesenchymal cell interactions and innervations play a part in the normal regulation of peribiliary glands and also in the proliferation of peribiliary galnds in hepatolithiasis.     

Interactions between epithelial and mesenchymal cells in intrahepatic peribiliary glands in normal and hepatolithiatic livers

The anatomy and pathology of the intrahepatic peribiliary glands were evaluated. In this study, we ultrastructuraly examined the peribiliary glands of normal and hepatolithiatic livers using common and serial ultrathin section observations. It is well known that these glands proliferate markedly in hepatolithiasis. These glands were composed of several acini surrounded by thickened and multilayered basement membranes, and there were mesenchymal cells (the majority were fibroblasts) in the periacinar fibrous connective tissue. Some cytoplasmic processes of acinar epithelial cells and mesenchymal cells in the periacinar connective tissue were in close contact with each other within the thickened and multilayered basement membranes. Such cell-to-cell interaction was most frequent in cases of hepatolithiasis, in which peribiliary glands proliferated markedly. In hepatolithiatic livers, some unmyelinated nerve fibers or axonal button profiles were in close contact with periacinar mesenchymal cells and also with cytoplasmic processes of glandular epithelial cells. Such contacts were rare in normal livers. These findings suggest that such epithelial and mesenchymal cell interactions and innervations play a part in the normal regulation of peribiliary glands and also in the proliferation of peribiliary glands in hepatolithiasis.     

Experimental liver cysts induced by 2-acetylaminofluorene

Liver cyst formation was studied serially in an experimental model in which rats were fed a diet containing 0.02% 2-acetylaminofluorene, a carcinogen, for 6 weeks, followed by a normal diet for 42 weeks. Cysts appeared in the portal tracts at the 12th week, by which time the intrahepatic bile ducts had also proliferated and dilated. Some of the dilated bile ducts were cavernous or multicystic and appeared to represent a transitional form between the bile duct dilatation and cystic formation. After 20 weeks cysts were observed in the majority of rats. The number and the size of cysts in the liver increased with time; after 40 weeks, there were up to 20 cysts as large as 15 mm in diameter. Carcinoma or cirrhosis did not develop in this model. Indocyanine green dye injected intravenously did not accumulate in the cysts, which denies the possibility of communication between cysts and the bile duct. Scanning electron microscopy demonstrated that the cysts were composed of a few intercommunicating cavities and were lined with epithelial cells similar to those of the intrahepatic bile duct, which had numerous microvilli and a central cilium. These observations suggest that liver cysts originate in the bile duct.