Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Borderline nodule (BN) in the cirrhotic liver is considered to be a precancerous lesion leading to hepatocellular carcinoma (HCC). We investigated the distribution of cytokeratin 19 (CK 19)-positive biliary cells, recognizable by a monoclonal antibody AE1, in normal livers, chronic active hepatitis, cirrhosis, BN, and small HCC. The CK 19-positive biliary cells in the hepatic parenchyma were clearly divisible into two types (I and II). Type I cells were located within the hepatic parenchyma as small clusters forming small tubules (intraparenchymal ductules). Type II cells were bile ductules located in the peripheral rim of the hepatic lobules or hepatocellular lesions (peripheral ductular reaction) and were continuous with proliferated bile ductules in fibrous septae or portal tracts. In chronic active hepatitis and regenerative nodules of cirrhosis, a few type I cells and a variable number of type II cells were present. In the BN, all cases harbored a few type I cells as well as a variable number of type II cells. The type II cells in the BN were fewer in number and more randomly distributed than those in chronic active hepatitis and cirrhosis. Malignant foci in some BNs lacked CK 19-positive biliary cells. In small HCC, no CK 19-positive biliary cells were found; instead, AE1-positive HCC cells were present in three cases (17%). Although a great majority of type I cells corresponded to intraparenchymal ductules, some type I cells in the BN were composed of rather large tubules considered as interlobular bile ducts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distribution of cytokeratin 19-positive biliary cells in cirrhotic nodules, hepatic borderline nodules (atypical adenomatous hyperplasia), and small hepatocellular carcinomas. 756 33

It has been reported that cytokeratin 19 fragment (CYFRA 21-1) is superior to tissue polypeptide antigen (TPA) as a tumor marker, although there is a high correlation between CYFRA 21-1 and TPA levels in patients with lung cancer. We investigated correlations between these tumor markers in patients with non-malignant diseases. Marked correlations were found between CYFRA 21-1 and TPA levels in healthy subjects (n = 31), non-insulin-dependent diabetes mellitus (n = 160) and hemodialysis patients (n = 83) (range of r-value = 0.90-0.93, P < 0.0001). However in liver cirrhosis patients (n = 36), only a weak correlation was found (r = 0.39, P < 0.0001) and there were correlations between only TPA and both aspartate aminotransferase and alanine aminotransferase levels (r2 = 0.48 and 0.36, P < 0.0001). The elevated TPA levels in liver cirrhosis patients may be related to the decreased specificity of TPA as a tumor marker.
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PMID:Correlation between serum cytokeratin 19 fragment and tissue polypeptide antigen levels in patients with non-malignant diseases. 962 Apr 68

Hepatocytes of normal adult liver express cytokeratins (CKs) 8/18, but bile duct cells additionally contain CK7/19. We have previously demonstrated the frequent occurrence of foci of altered hepatocytes in association with hepatic tumors in humans and provided evidence for a preneoplastic nature of the focal lesions. In this study, we investigated the CK expression in both the preneoplastic lesions and extrafocal parenchyma. Sixty-seven explanted livers with cirrhosis or advanced fibrosis harboring preneoplastic focal lesions, with or without hepatitis B virus (HBV) infection, as well as 9 livers with HBV-associated fulminant hepatitis, were studied for the expression of CK7/8/14/18/19. Five livers from woodchucks infected with the woodchuck hepatitis virus (WHV) were also investigated. Glycogenotic clear hepatocytes were negative or weakly positive for CK8/18, while amphophilic hepatocytes were strongly positive for these CKs, the changes being associated with marked reduction and increase, respectively, of highly organized membranous components in their cytoplasm. This allows the distinct recognition of the clear-cell and clear-cell-dominant preneoplastic lesions in the human and woodchuck livers. In ground-glass hepatocytes expressing viral antigens, an unusual accumulation of CK8/18 was observed, but there was no evidence of preferential necrosis of ground-glass hepatocytes. Many CK7- and CK19-positive ductular (oval) cells were found in extrafocal liver tissue, but only rarely were they present within focal lesions.
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PMID:Cytokeratin expression is reduced in glycogenotic clear hepatocytes but increased in ground-glass cells in chronic human and woodchuck hepadnaviral infection. 969 96

A 59-year-old woman presented with epigastric pain and weight loss. Ultrasound, computed tomography, and magnetic resonance imaging scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. The tumor was subsequently resected, and histopathology showed a poorly differentiated adenocarcinoma immunoreactive for CA 19-9 and cytokeratin 19. In the absence of any other clinically detectable primary tumor, the lesion was diagnosed as a peripheral intrahepatic cholangiocarcinoma. In addition, multiple bile duct hamartomas were found in the surrounding parenchyma. The tumor was unrelated to Caroli disease, primary sclerosing cholangitis, ulcerative colitis, or nonbiliary cirrhosis, as demonstrated by further clinical and histopathologic investigations, but probably was associated with the presence of multiple bile duct hamartomas. To our knowledge, this is the eighth reported case of a cholangiocarcinoma associated with multiple bile duct hamartomas.
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PMID:Cholangiocarcinoma occurring in a liver with multiple bile duct hamartomas (von Meyenburg complexes). 1107 31

The existence of a liver stem cell population has only gained credence recently, following the results of animal experiments. These cells are thought to reside in the terminal bile ductules (canals of Hering). Hepatocyte division is responsible for liver regeneration after most causes of injury. However, stem cells may contribute to hepatocyte regeneration, or even take over this role if the liver injury is severe and associated with an impairment of hepatocyte proliferation as in cirrhosis or submassive/massive necrosis, due to drugs, toxins or viruses. "Oval" cells are the descendants of the stem cells and are found in the portal and periportal regions in experimental animals within days of the liver injury. These cells proliferate to form narrow ductules, which may stain positively for biliary cytokeratins CK 19, and radiate out into the damaged parenchyma. Both in vitro and in vivo animal studies now suggest that oval cells can differentiate into bile ductular cells or hepatocytes to allow repopulation of the injured liver. As the oval cells differentiate into hepatocytes they may show positive staining for pyruvate kinase isoenzyme L-PK, albumin and alpha-fetoprotein. There is also growing evidence that bone marrow stem cells may contribute to liver regeneration. The possible involvement of hepatic stem cells in the development of dysplastic nodules, hepatocellular carcinoma and cholangiocarcinoma has been suggested but remains highly controversial. Oval cell isolation and culture techniques, together with stem cell transplantation strategies, may in the future provide novel treatments for individuals with inherited and acquired hepatic disorders.
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PMID:Hepatic stem cells: a review. 1135 43

In the liver, neural cell adhesion molecule (NCAM) is a marker of immature cells committed to the biliary lineage and is expressed by reactive bile ductules in human liver diseases. We investigated the possible role of NCAM in the development of intrahepatic bile ducts and aimed at determining whether immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases. Therefore, we performed immunohistochemistry for NCAM and bile duct cell markers cytokeratin 7 and cytokeratin 19 on frozen sections of 85 liver specimens taken from 14 fetuses, 10 donor livers, 18 patients with congenital liver diseases characterized by ductal plate malformations (DPMs), and 43 cirrhotic explant livers. Duplicated ductal plates and incorporating bile ducts during development showed a patchy immunoreactivity for NCAM, while DPMs were continuously positive for NCAM. Bile ducts showing complete or patchy immunoreactivity for NCAM were found in cirrhotic livers, with higher frequency in biliary than in posthepatitic cirrhosis. Our results suggest that NCAM may have a function in the development of the intrahepatic bile ducts and that NCAM-positive immature biliary cells can contribute to the repair of damaged bile ducts in chronic liver diseases.
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PMID:Expression of neural cell adhesion molecule in human liver development and in congenital and acquired liver diseases. 1168 52

Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3. These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.
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PMID:Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum. 1171 Jun 92

Combined hepatocellular-cholangiocarcinoma (CHC) forms a small but significant proportion of primary liver carcinomas. However, its diagnostic features are not well established, and this has possibly contributed to the variability in its reported clinical outcome in the literature. Many such tumors with features intermediate between hepatocellular carcinoma and cholangiocarcinoma (CC) may have been considered CC in the past based on positivity for "biliary differentiation" cytokeratins and the lack of availability of highly sensitive and specific hepatocellular markers. The utility of in situ hybridization for albumin mRNA, a recently available sensitive and specific hepatocellular marker, has not been reported in CHC. We investigated 27 CHCs with regard to their histomorphologic spectrum and association of these morphologies with immunohistochemical staining for different cytokeratins (CK7, CK19, and CK20; AE1; Cam 5.2), epithelial membrane antigen, polyclonal carcinoembryonic antigen and alpha-fetoprotein, and in situ hybridization for albumin mRNA. All 27 tumors contained areas morphologically intermediate between hepatocellular carcinoma and CC (transitional-type tumors), and in each case such areas formed at least 25% of the tumor. Nine (33%) tumors showed areas with "antler-like" morphology, a feature not previously described in CHC. Twenty-two of 23 tumors (96%) showed positive signals on in situ hybridization for albumin mRNA. Positivity for both hepatocellular (albumin mRNA) and biliary (keratin immunohistochemical profile) markers confirmed the light microscopic impression of biphenotypic differentiation in these tumors. Immunohistochemical positivity for all cytokeratins (except CK7) and epithelial membrane antigen, as well as the expression of albumin mRNA by in situ hybridization, did not show significant differences between hepatocellular carcinoma and CC-like areas. Based on the cytokeratin profile and results on polyclonal carcinoembryonic antigen/alpha-fetoprotein alone, many such tumors would be classified as CC. However, the positivity for albumin mRNA by in situ hybridization proves that such an interpretation would not have been accurate. Clinically, CHCs showed many differences from pure hepatocellular carcinoma, including the absence of cirrhosis (0 of 27), rarity of serum hepatitis B or C marker positivity (4 of 27), and normal to only mildly elevated serum alpha-fetoprotein levels (median 187 ng/mL). The tumor followed an aggressive clinical course, with overall 3-and 5-year survival rates of 30% and 18%, and in the resected cases of 38% and 24%, respectively.
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PMID:Combined hepatocellular-cholangiocarcinoma: a histopathologic, immunohistochemical, and in situ hybridization study. 1217 85

Cirrhosis is considered to be the precursor of most hepatocellular carcinomas. To gain insight into the early molecular mechanisms of liver carcinogenesis, this study compared, using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), the expression levels of 31 selected genes in normal livers, cirrhotic nodules, and hepatocellular carcinomas. Since cirrhosis is composed of a mixture of polyclonal and monoclonal nodules, gene expression levels were also compared according to the clonal status of the cirrhotic nodules. The expression of eight of the 31 genes studied was significantly increased (NEGF2, ANGPT1, ARF, KRT19, SFN, CLDN4, MMP7, and ETV4) in cirrhotic nodules compared with normal liver, while only one was decreased (LYVE1). The same trend of variation was observed in cirrhosis and hepatocellular carcinomas for all of these genes except KRT19. When gene expression variation was compared according to the clonal status of cirrhotic nodules, only the LYVE1 expression level was significantly different. The LYVE1 gene expression level decreased progressively from polyclonal cirrhotic nodules to monoclonal cirrhotic nodules (polyclonal nodules 0.39 +/- 0.25; monoclonal nodules 0.20 +/- 0.14; p < 0.05) and to hepatocellular carcinoma (0.07 +/- 0.1). In conclusion, this study highlights the fact that among genes strongly dysregulated in hepatocellular carcinoma, some are already abnormally expressed in cirrhosis. The decrease in the expression level of one of these genes, LYVE1, was associated with monoclonality in cirrhotic nodules.
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PMID:Quantitative RT-PCR in cirrhotic nodules reveals gene expression changes associated with liver carcinogenesis. 1451 43

Cholangiocarcinoma (CCA) is a lethal disease, afflicting many thousands the world over. Human CCA develops through a multi-step progression model, preceded by the onset of dysplasia in the cholangiolar ductal epithelium. An animal model of multi-step carcinogenesis in the biliary tree will enable the study of genetic changes in human CCA, and provide an avenue for chemoprevention strategies. We describe an oral thioacetamide (TAA)-induced model of rat CCA that recapitulates the histologic progression of human CCA. Male Sprague-Dawley (SD) rats (n = 170), weighing 350 +/- 20 g, were used in this study. Drinking water with TAA 300 mg/l was administered orally, and the liver was harvested and examined histologically at weekly intervals, beginning at 5 weeks after initiation of TAA. Harvested tissues were formalin-fixed and paraffin embedded for morphologic and immunohistochemical studies. Multifocal bile ductular proliferation with intestinal metaplasia (presence of goblet cells) and increasing histologic atypia (biliary dysplasia) was observed by the 9th week of TAA administration. Biliary cytokeratin (CK19)-expressing invasive intestinal-type CCA with stromal desmoplasia was evident at the 16th week, and by the 22nd week, the yield rate for CCAs had increased to 100%. Invasive CCAs preceded the development of hepatic cirrhosis by at least 4 weeks; the earliest incidence of hepatic fibrosis was observed beginning at 20 weeks post-TAA administration. The progression from normal cholangioles to biliary dysplasia to invasive CCA was accompanied by up-regulation of the proto-oncogenes c-met and c-erbB-2, tyrosine kinase receptors over-expressed in human CCAs. The study was terminated at 6 months, at which time no systemic metastases or deaths were observed. Oral administration of TAA in drinking water to male SD rats provides a reproducible animal model for development of CCA with a high yield rate. In particular, the presence of biliary dysplasia beginning at the 9th week, which progresses to invasive CCA, mimics the multi-step model of human CCA. The TAA rat model may serve as a powerful pre-clinical platform for therapeutic and chemoprevention strategies for human CCA.
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PMID:Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. 1465 42


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