Peribiliary cysts: a hitherto poorly recognized disease.
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Cysts↗
Biomedical subjects
Y Nakanuma
Publications and source records attributed to Y Nakanuma.
Hepatocellular carcinoma arising in non-alcoholic steatohepatitis.
The incidence and significance of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH) has not been previously evaluated in detail. We recently experienced a case of NASH with multicentric HCC in a female patient. At the age of 58 years, the patient was diagnosed with non-insulin-dependent diabetes mellitus, treated by insulin therapy. The patient did not drink alcohol. She was negative for all serological markers of hepatitis B and C virus infection. Because of liver dysfunction, a needle biopsy was performed at the age of 62 years, and pathological findings, such as fatty change, Mallory's body, nuclear glycogen and pericellular fibrosis, suggested a diagnosis of NASH. Subsequently, four nodules were detected in the liver by imaging. Liver biopsies were performed from each nodule. One nodule was pathologically diagnosed as a pseudolymphoma, while three other nodules were moderately differentiated HCC (10 years after the diagnosis of non-alcoholic steatohepatitis), well-differentiated HCC (11 years later) and dysplastic nodule (11 years later), suggesting multicentric occurrence of HCC. This case suggests that HCC could be a late complication of NASH.
Biopsy, Needle↗
Enhanced expression of basement-membrane-type heparan sulfate proteoglycan in tumor fibro-myxoid stroma of intrahepatic cholangiocarcinoma.
To investigate the molecular mechanism for enhanced fibrous stroma formation in intrahepatic cholangiocarcinoma (ICC), we surveyed the expression pattern of basement-membrane-type heparan sulfate proteoglycan (HSPG; also known as perlecan) at the core protein and the mRNA level in ICC as well as in other liver neoplasms and reactive hepatic diseases. Immunohistochemistry of paraffin-embedded liver sections with hyaluronidase pretreatment showed that HSPG was present in small amounts in normal liver around the bile ducts and the blood vessels within the portal area. There was no evident expression within the hepatic lobules. Intense immunoexpression of HSPG was seen in the tumor-specific fibro-myxoid stroma of ICC and metastatic liver cancer originating from the colon. However, tumor-specific stroma of hepatocellular carcinomas showed little or no expression of HSPG. At the mRNA level, signals for HSPG were found in tumor cells of cholangiocarcinoma and metastatic colonic carcinomas, and in myofibroblasts in the tumor fibro-myxoid-specific stroma. From immunoprecipitation and reverse transcription-polymerase chain reaction (RT-PCR) analyses, a cultured human intrahepatic cholangiocarcinoma cell line (CCKS1), was found to express high levels of HSPG core protein and mRNA. These findings suggest that biliary and metastatic colon carcinoma cells as well as stromal myofibroblasts have a potential for HSPG production. In order to investigate the growth, invasion and metastatic ability of ICC, further study of the 'self-made' stromal component of ICC may provide a new approach.
Adult↗
Spontaneous occurrence of chronic non-suppurative destructive cholangitis and antimitochondrial autoantibodies in MRL/lpr mice: possible animal model for primary biliary cirrhosis.
MRL/MP mice bearing the lymphoproliferative gene lpr (known as MRL/MP-lpr/lpr or MRL/Ipr mice) are known to spontaneously develop severe autoimmune diseases such as glomerulonephritis, arteritis and arthritis at an early stage of their life. They have also been reported to develop severe sialadenitis, suggesting that this mouse could be a model for Sjögren's syndrome. Primary biliary cirrhosis, an autoimmune disease characterized by chronic non-suppurative destructive cholangitis and the occurrence of antimitochondrial antibodies, is frequently associated with Sjögren's syndrome. In this study, we examined whether cholangitis and/or antimitochondrial antibodies occur in this mouse model, using more than 100 young and old MRL/Ipr mice. We frequently found portal inflammation associated with cholangitis of small intrahepatic bile ducts, especially in older mice. There was also infiltration of inflammatory cells (monocytes) as well as CD4-positive T cells. Epithelioid granuloma and bile-duct loss were also occasionally found. These histological features resemble primary biliary cirrhosis. In addition, antimitochondrial antibodies were shown by immunocytochemistry to be present in the sera of MRL/Ipr mice. There is currently no established animal model for primary biliary cirrhosis. Therefore, further studies on MRL/Ipr mice, with respect to pathogenesis of primary biliary cirrhosis, are warranted.
Animals↗
Expression of endogenous galectin-1 and galectin-3 in intrahepatic cholangiocarcinoma.
Galectins, a family of beta-galactoside-binding animal lectins, might be involved in tumor progression. In this study, the expression patterns of galectin-1 and -3 were examined immunohistochemically in intrahepatic cholangiocarcinoma (ICC), with emphasis on its development and progression as well as its histopathologic features, by use of samples of normal intrahepatic bile duct (n = 20), biliary epithelial dysplasia (n = 15), ICC (n = 40), and a cholangiocarcinoma cell line, CCKS1. In normal intrahepatic bile ducts, galectin-3 was constitutively but weakly expressed, whereas galectin-1 was not expressed. In hepatolithiasis, biliary epithelial dysplasia was strongly positive for galectin-3 but negative for galectin-1. Galectin-3 was frequently and strongly expressed in the cytoplasm of well-differentiated ICCs, and its expression was significantly decreased and less intense or even absent in poorly differentiated ICCs. Galectin-1 was expressed in carcinoma cells in ICC, and its incidence and extent were correlated with histologic dedifferentiation of ICC. Proliferative cell nuclear antigen (PCNA) labeling index (LI) was higher in ICC cases positive for galectin-1 than in those that were negative. Galectin-1 was strongly expressed in cancerous stroma of ICC, and this stromal expression was related to histologic dedifferentiation of ICC. In the carcinoma cell line CCKS1, galectin-1 and -3 were expressed in the cytoplasm of carcinoma cells, and galectin-1 was additionally detected in the culture medium. These results suggest that galectin-1 was newly expressed on carcinoma cells of ICC, and its overexpression seems to be associated with neoplastic progression and proliferative activities, and the expression of galectin-1 in cancerous stroma may also be related to the progression of ICC. Galectin-3 expression in epithelial cells is up-regulated in the preneoplastic and early neoplastic stages of ICC, although galectin-3 tends to disappear at later stages of ICC. HUM PATHOL 32:302-310.
Adult↗
Molecular identification of bacterial 16S ribosomal RNA gene in liver tissue of primary biliary cirrhosis: is Propionibacterium acnes involved in granuloma formation?
The etiopathogenesis of primary biliary cirrhosis (PBC) remains speculative. Epithelioid granulomas are often found in the vicinity of damaged interlobular bile ducts in PBC, raising the possibility of a reaction to microbial materials. In this study, we tried to detect and identify bacterial DNA within granulomatous lesions in PBC. Using liver sections from 9 patients with PBC and 13 control livers, granuloma in portal tracts, portal tracts without granuloma, and adjacent hepatic parenchyma were selectively microdissected from sections, and then DNA was extracted from them. First, part of the bacterial 16S ribosomal RNA (rRNA) gene was amplified from DNA samples extracted from 5 PBC and 6 control livers, and their amplicons were sequenced for the identification of bacterial species. Several indigenous bacteria were identified. Among them, Propionibacterium acnes (P. acnes) was detected as a major clone in 20% to 50% of sequenced clones from granuloma of PBC, but the detection rate of P. acnes was 0% to 20% in those cloned from adjacent hepatic parenchyma of PBC. Then, a P. acnes-specific PCR was performed using all microdissected samples. Distinct PCR products were identified in epithelioid granuloma in all 9 PBC cases. The result that P. acnes DNA is present as a major clone in granulomas of PBC, suggest that P. acnes is involved in the pathogenesis of granuloma in PBC.
DNA, Bacterial↗
Human REG I gene is up-regulated in intrahepatic cholangiocarcinoma and its precursor lesions.
The Reg I gene (regenerating gene) and its product (Reg protein) are a regenerating and/or proliferating factor(s) of pancreatic islet cells. The ectopic expression of REG Ialpha was shown in colorectal carcinomas, suggesting that REG Ialpha is related to their carcinogenesis. In this study, we examined the expression of REG I in intrahepatic cholangiocarcinoma (ICC) and its precursor lesion (biliary dysplasia). By polymerase chain reaction and in situ hybridization (ISH) studies using a total of 16 fresh liver specimens, REG Ialpha mRNA was demonstrated in 6 of 11 (55%) ICC cases, but in 0 of 5 (0%) normal livers. Immunohistochemistry for REG I protein was performed in 100 formalin-fixed, paraffin-embedded sections obtained from the 18 cases of ICC alone, 45 hepatolithiasis with ICC (n = 19) or biliary dysplasia (n = 26), 21 hepatolithiasis alone (all with hyperplasia), and 16 normal livers. In ICC, the expression of REG I protein was significantly dependent on the histologic differentiation; 12 of 13 (92%) cases in papillary and well-differentiated, 6 of 16 (38%) cases in moderately differentiated, and 0 of 8 (0%) cases in poorly differentiated types. Moreover, in the lesions of hyperplasia, low-grade dysplasia, and high-grade dysplasia in hepatolithiasis, REG I protein was expressed in 4 of 21 (19%), 7 of 12 (58%), and 13 of 14 (93%) cases, respectively. In normal liver, intrahepatic bile ducts were constantly negative for REG I protein. These findings suggest that neoexpression of REG I is a good marker for biliary mucosa at risk for development of ICC, and also that REG I plays a role in the early stages of biliary carcinogenesis, probably via a cell-proliferative effect.
Bile Duct Neoplasms↗
Immunoglobulin gene usage and immunohistochemical characteristics of human monoclonal antibodies to the mitochondrial autoantigens of primary biliary cirrhosis induced in the XenoMouse.
The immunodominant antimitochondrial antibody (AMA) response in primary biliary cirrhosis (PBC) is directed against the E2 component of pyruvate dehydrogenase (PDC-E2). The nature of the clonal selection process is unclear, and to address this issue, we took advantage of a transgenic technology, XenoMouse, that contains 80% of the human immunoglobulin (Ig) variable gene repertoire and can produce high-affinity human antibodies to virtually any immunogen without evidence of clonal bias. We immunized mice with PDC-E2 to obtain 13 HmAbs, including 4 IgG(2) and 9 IgM isotypes. Immunoglobulin gene analysis was unique and demonstrated a clonal bias; the immunoglobulin gene usage was considerably different from other antibody responses analyzed in XenoMouse systems. Four of the 13 mAbs recognized the inner lipoyl domain of PDC-E2, 2 of 13 recognized the entire PDC-E2 molecule, 4 of 13 recognized PDC-E2 and OGDC-E2, 1 of 13 recognized OGDC only, 1 recognized BCOADC-E2 only, and 1 recognized an unidentified 100-kd mitochondrial protein. Immunohistochemical staining using these HmAbs produced mitochondrial staining of septal bile ducts in both PBC and control livers. Ig gene analysis showed that 7 of 13 HmAbs used the V(H)3 and 4 of 13 used VH4 gene repertoire, respectively. Three of 7 V(H)3 antibodies used the same Ig VH3-21 gene family found in human AMA from patients with PBC. The CDRs of these autoantibodies were slightly mutated when compared with the sequences present within the Ig germline genes. In conclusion, the XenoMouse not only recapitulates the unique specificity and restriction of PBC patients, but indicates that the autoantibodies are derived from a restricted clonal selection process. Such data suggest that the original immunogen leads to somatic mutation without subsequent development of determinant spreading.
Amino Acid Sequence↗
Intraductal papillary neoplasia of the liver associated with hepatolithiasis.
Intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk (intraductal papillary neoplasia of liver [IPN-L]) resembling intraductal papillary mucinous neoplasm of pancreas is occasionally associated with hepatolithiasis. In this study, 136 cases of hepatolithiasis in Taiwan, between January 1998 and March 2000, and an additional 21 cases of IPN-L before December 1998, were examined histologically. IPN-L was found in 41 of 136 hepatolithiasis cases (30.1%). Sixty-two IPN-L cases (42 women and 20 men; age range, 59.8 +/- 10 years) were divided into 4 types (type 1, IPN-L with low-grade dysplasia, 23 cases; type 2, IPN-L with high grade dysplasia, 11 cases; type 3, IPN-L with in situ and microinvasive carcinoma, 13 cases; and type 4, IPN-L of types 2 and 3 with distinct invasive carcinoma, 15 cases). Intraductal spreading and glandular involvement were commonly observed in all types. About half of types 3 and 4 cases had mucobilia, and mucinous carcinoma was variably found in two thirds of group 4 patients. IPN-L frequently showed variable gastroenteric differentiation such as goblet cells and foveolar and colon-like metaplasia. IPN-L with goblet cells and colon-like metaplasia was frequently associated with overproduction of mucin and mucobilia (P <.01). In Japan, IPN-L was not frequent in hepatolithiasis (12 of 135 cases). In conclusion, IPN-L forms a spectrum of biliary neoplasm in hepatolithiasis. It often displays variable gastroenteric metaplasia and significant intraductal spread. IPN-L tends to progress to mucinous carcinoma. Formerly reported "mucin-producing intrahepatic cholangiocarcinoma" with a favorable prognosis is included in IPN-L.
Adult↗
Intrahepatic cholangitis and arteritis after transcatheter arterial embolization in a patient with tumor-like lesion-associated autoimmune hepatitis.
Autoimmune hepatitis is a chronic liver disease characterized by immune-mediated, progressive hepatocellular damage, although the target autoantigen remains speculative. Intrahepatic biliary lesions are not a feature of this disease. We describe herein a female patient, 57 years, with autoimmune hepatitis who developed hepatic regenerative mass after acute exacerbation of hepatitis. This hepatic regenerative mass was clinically diagnosed as hepatocellular carcinoma and was surgically resected after transcatheter arterial embolization therapy. Widespread nonsuppurative destructive granulomatous cholangitis as well as necrotizing, granulomatous arteritis of the intrahepatic small arteries were found in the surgically resected hepatic regenerative mass. The bile duct lesions were histologically and immunohistochemically very similar to the granulomatous cholangitis of primary biliary cirrhosis. We would like to propose that these unusual lesions in the intrahepatic bile ducts and intrahepatic arteries represent a reaction of this patient to an anti-cancer drug included in chemoembolization. No such cases have been reported so far.
Arteritis↗
A case report of early idiopathic portal hypertension.
We report herein a case (46 years, female) of very early idiopathic portal hypertension. During an examination for in situ uterine cervical cancer, splenomegaly and hypersplenism were incidentally found. CT and MRI showed a nonatrophic liver with dilated portal veins and marked splenomegaly. The portal venous blood flow was increased, while portal venous blood pressure was not high. The spleen (1,220 g) showed hyperplasia of white pulp and congestion. The lobular architecture of the liver was well-preserved, and the subcapsular regions were not atrophic or dropped out. The portal tracts were not fibrotic, and portal veins were neither stenotic nor sclerotic. Instead, lymphoid cell infiltrations were found in about half the portal tracts, and there was subendothelial mononuclear cell infiltration of small portal vein branches. The hepatic lobules showed non-specific reactive change. This case suggests that early hepatic changes recognizable histologically in this disease are lymphoid cell infiltration of the portal tract and of subendothelial regions of portal vein branches, and nonspecific lobular hepatitis. These hepatic changes, as well as marked splenomegaly, may represent an altered immunophenomenon of this disease.
Carcinoma in Situ↗
Pathology and pathogenesis of idiopathic portal hypertension with an emphasis on the liver.
Idiopathic portal hypertension (IPH) is characterized by a long-standing presinusoidal portal hypertension of unknown etiology in adults. Some unidentified agent(s) affect(s) the intrahepatic small portal veins or portal tracts. Immunological disturbance, thromboembolism, infectious etiology and/or increased fibrogenesis in portal tracts are suspected as being candidates for the primary agent(s). During the long clinical course of IPH, several pathological changes may occur, including subcapsular parenchymal atrophy, atrophy of the liver, portal and parenchymal fibrosis, and portal venous phlebosclerosis and thrombosis. The last-named of these lesions is mostly found in patients with a history of splenectomy. Subcapsular parenchymal and hepatic atrophy may result from a hepatocellular dropout via apoptosis or necrosis because of intrahepatic hemodynamic disturbances, particularly chronic portal venous blood insufficiency. Pericellular fibrosis and thin fibrous septa are also frequently found and associated with activated perisinusoidal cells positive for smooth muscle actin. At the same time, vague nodular hyperplasia of hepatocytes not surrounded by fibrous septa is not infrequently seen. It may resemble nodular regenerative hyperplasia, partial nodular transformation, or focal nodular hyperplasia. However, liver cirrhosis does not occur even at the terminal stage. Taking these findings into consideration, a new staging of IPH with a combination of hepatic parenchymal atrophy and portal venous thrombosis was proposed: non-atrophic liver without subcapsular parenchymal atrophy (stage I), non-atrophic liver with subcapsular parenchymal atrophy (stage II), atrophic liver with subcapsular parenchymal atrophy (stage III), and portal venous occlusive thrombosis (stage IV). IPH livers are likely to progress from stage I to stage III. Stage IV, which occurs relatively late, has a poor prognosis. This staging is applicable to clinical and autopsy cases without any histological data.
Adult↗
Hepatic sarcoidosis with vanishing bile duct syndrome, cirrhosis, and portal phlebosclerosis. Report of an autopsy case.
A few cases of sarcoidosis are associated with progressive liver disease, with a wide variety of clinicopathologic features. Herein, we report an autopsy case (65-year-old man). During an examination for liver dysfunction, cirrhosis with cholestatic dysfunction and splenomegaly were found. Needle liver biopsy revealed cirrhosis with lymphocytic piecemeal necrosis, dense septal fibrosis, and ductopenia. In addition, noncaseating epithelioid granuloma was also seen in the periportal region. Ductal enzymes and immunoglobulin M (IgM) levels were elevated, although antimitochondrial antibodies were negative. Instead, angiotensin-converting enzyme was elevated. He died of pulmonary failure and lung cancer. The autopsy liver (1,220 g) showed multinodular cirrhosis with broad and dense septa that divided the parenchyma. Mild lymphoid cell infiltration was seen in the periportal region. About a half of the interlobular bile ducts were lost, and the remaining bile ducts showed prominent periductal fibrosis, resembling sclerosing cholangitis. Interestingly, a few interlobular bile ducts showed chronic nonsuppurative cholangitis with epithelioid granulomas. Intrahepatic portal veins showed luminal narrowing with prominent phlebosclerosis. Hepatobiliary pathologies that resemble primary biliary cirrhosis and primary sclerosing cholangitis and that are followed by vanishing bile duct syndrome, chronic active hepatitis-related cirrhosis, and intrahepatic portal venous phlebosclerosis occur in a single case of sarcoidosis.
Bile Ducts, Intrahepatic↗
Myxedema accompanied by huge portal-systemic shunt without portal hypertension.
A 43-year-old woman with a huge portal-systemic shunt accompanied by myxedema showed slow speech and behavior. Several imaging studies revealed a bold portal-systemic shunt from the splenic vein to the left renal vein. In addition, hypothyroidism caused by chronic thyroiditis was diagnosed, and synthesized thyroxine replacement was effective for the symptoms. However, the serum ammonia and indocyanin green retention remained in the abnormal range, nevertheless the portal vein pressure was normal and findings of liver cirrohsis were not recognized histologically. Surgical shunt closure was performed, resulting in normalized serum ammonia levels and serum branched chain amino acids /aromatic amino acids ratio, and improvement of the ammonia tolerance test.
Adult↗
[Autoimmune liver diseases and their borderline lesions from pathologic standpoint of view].
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Autoimmune Diseases↗
Immunohistochemical analysis of cell-matrix adhesion molecules and their ligands in the portal tracts of primary biliary cirrhosis.
Intraepithelial migration of lymphoid cells (epitheliotropism) through the basement membrane of the bile duct is a key event in the development of chronic non-suppurative destructive cholangitis (CNSDC) and eventual immune-mediated bile duct loss in primary biliary cirrhosis (PBC). Cell-to-cell and cell-to-extracellular matrix proteins may play an important role in the development of CNSDC. To address the events of epitheliotropism in CNSDC, the expression of cell-matrix adhesion molecules such as integrins alpha1, alpha3, alpha4, alpha5, and alpha6 and the distribution of fibronectin, laminin, and collagen type IV were studied immunohistochemically, with emphasis on both infiltrating lymphocytes and the bile ducts, in frozen sections from 15 PBC cases and 34 controls (chronic viral hepatitis, extrahepatic biliary obstruction, and normal liver). In PBC and chronic viral hepatitis, most of the infiltrating lymphoid cells expressed integrin alpha4, while such expression was less common in extrahepatic biliary obstruction and normal liver. A biliary basement membrane-like structure was delineated by immunostaining of collagen type IV and laminin in PBC and controls. On the basement membrane of CNSDC, fibronectin, a ligand of integrin alpha4, was strongly and frequently expressed in PBC, while such expression on the biliary basement membrane was rare in other controls. These results suggest that increased fibronectin expression on the biliary basement membrane and integrin alpha4-fibronectin interaction facilitate adhesion and the penetration of infiltrating alpha4-expressing lymphocytes into the biliary epithelial layer in PBC.
Antigens, CD↗
Comparative immunoreactivity of anti-trifluoroacetyl (TFA) antibody and anti-lipoic acid antibody in primary biliary cirrhosis: searching for a mimic.
Previous studies documenting the existence of cross-reactivity between the lipoated (but not unlipoated) forms of the inner lipoyl domain (E2L2) of PDC-E2 [the major autoantigen in Primary biliary cirrhosis (PBC)] and trifluoroacetylated (TFA) proteins, led us to hypothesize that PBC may be due to an initial insult with an environmental agent that cross-reacts with TFA. Therefore, we performed a comparative study of the reactivity of rabbit anti-TFA antibody and anti-lipoic acid (LA) antibody against the mitochondrial autoantigens of human PBC and various TFA and LA conjugated proteins. Whereas both anti-TFA and anti-LA reacted with PDC-E2, the wild-type lipoated form of E2L2, OGDC-E2, E3-BP and LA-KLH, neither reacted with BCOADC-E2 or the non-lipoated form of E2L2. Of interest was that while anti-TFA reacted with PDC-E2, TFA-RSA and LA-KLH, it failed to inhibit PDC-E2 enzyme function. In contrast, anti-LA demonstrated cytoplasmic and mitochondrial staining, and inhibited PDC enzyme activity. Hence, although considerable cross reactivity exists between anti-TFA and anti-LA, the molecular nature of the interaction is clearly different. One of 14 PBC sera reacted weakly with TFA-albumin, whereas four of 14 PBC sera reacted with LA-KLH. Immunohistochemically, both anti-TFA and anti-LA antibodies reacted focally with periportal hepatocytes and bile ducts in both PBC and controls. However, anti-LA produced much stronger focalized staining of the bile ducts of diseased liver. This study suggests that while anti-TFA antibody recognizes lipoic acid-linked enzymes and proteins, the epitope recognized differs from that of anti-LA antibody and PBC autoantibodies. It is unlikely that a response to TFA is the triggering event in PBC. Anti-LA antibodies share a higher degree of similarity to PBC sera providing suggestive evidence that anti-LA antibodies or anti-LA like antibodies (mimotopes) may help define the initiator of the autoimmune response.
Animals↗
Precancerous lesions of intrahepatic cholangiocarcinoma.
Intrahepatic cholangiocarcinoma (ICC), also known as cholangiocellular carcinoma or peripheral bile duct carcinoma, is an intrahepatic malignant tumor that consists of cells resembling the biliary epithelium. The proportion of ICC among primary hepatic malignancies is approximately 10% worldwide. Although the etiology and pathogenesis remain unclear in a great majority of cases, preceding pathologic conditions or etiologies in the development of ICC are known or suspected in a proportion of these patients. Some forms of ICC, such as those associated with hepatolithiasis or liver fluke infestation, are endemic in parts of the world, particularly in East Asia. ICC is reportedly a late complication of primary sclerosing cholangitis. Most of these preceding pathologic conditions are forms of chronic cholangitis, and longstanding inflammation, chronic injury, and regenerative hyperplasia of the biliary epithelium may be causally related to malignant transformation. Biliary epithelial dysplasia is encountered in the intrahepatic bile ducts both near and remote from ICC foci in the liver and near and remote from the chronically inflamed biliary tree. This lesion could be a precancerous lesion, and it shows telomerase activity and increased proliferative activities. Furthermore, congenital and developmental disorders of the biliary system, such as Caroli's disease, congenital hepatic fibrosis, and pancreatico-biliary malformation are occasionally associated with ICC. Benign biliary tumors, such as biliary papillomatosis, may eventually undergo malignant transformation. These lesions could be regarded as precancerous or borderline lesions. Some ICCs may also develop in nonbiliary viral cirrhosis. In the majority of cases of ICC, however, the etiology, pathogenesis, and developmental processes and precancerous lesions of the ICC remain unclear.
Bile Duct Neoplasms↗