Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventy-two long-surviving liver transplant recipients were evaluated prospectively, including a baseline allograft biopsy for weaning off of immunosuppression. Thirteen were removed from candidacy because of chronic rejection (n = 4), hepatitis (n = 2), patient anxiety (n = 5), or lack of cooperation by the local physician (n = 2). The other 59, aged 12-68 years, had stepwise drug weaning with weekly or biweekly monitoring of liver function tests. Their original diagnoses were PBC (n = 9), HCC (n = 1), Wilson's disease (n = 4), hepatitides (n = 15), Laennec's cirrhosis (n = 1), biliary atresia (n = 16), cystic fibrosis (n = 1), hemochromatosis (n = 1), hepatic trauma (n = 1), alpha-1-antitrypsin deficiency (n = 9), and secondary biliary cirrhosis (n = 1). Most of the patients had complications of long-term immunosuppression, of which the most significant were renal dysfunction (n = 8), squamous cell carcinoma (n = 2) or verruca vulgaris of skin (n = 9), osteoporosis and/or arthritis (n = 12), obesity (n = 3), hypertension (n = 11), and opportunistic infections (n = 2). When azathioprine was a third drug, it was stopped first. Otherwise, weaning began with prednisone, using the results of corticotropin stimulation testing as a guide. If adrenal insufficiency was diagnosed, patients reduced to < 5 mg/day prednisone were considered off of steroids. The baseline agents (azathioprine, cyclosporine, or FK506) were then gradually reduced in monthly decrements. Complete weaning was accomplished in 16 patients (27.1%) with 3-19 months drug-free follow-up, is progressing in 28 (47.4%), and failed in 15 (25.4%) without graft losses or demonstrable loss of graft function from the rejections. This and our previous experience with self-weaned and other patients off of immunosuppression indicate that a significant percentage of appropriately selected long-surviving liver recipients can unknowingly achieve drug-free graft acceptance. Such attempts should not be contemplated until 5-10 years posttransplantation and then only with careful case selection, close monitoring, and prompt reinstitution of immunosuppression when necessary.
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PMID:Weaning of immunosuppression in long-term liver transplant recipients. 783 42

The authors measured immunoenzymatically circulating intercellular adhesion molecule-1 (cICAM-1) concentration in 135 patients with liver disease of either viral or toxic etiology: 13 had acute hepatitis; 58 had mild chronic liver disease; and 64 had cirrhosis (superimposed in 30 by hepatocellular carcinoma). Forty patients with extrahepatic diseases (19 with malignancies) and 28 healthy blood donors were tested as controls. One-way analysis of variance demonstrated a significant variability of cICAM-1 concentration among groups (F = 76.67, P < .0001), the highest value being recorded in acute hepatitis (Bonferroni's test for pairwise comparisons, P < .01). Total bilirubin showed a strong correlation with cICAM-1 (R = 0.766, P < .001). By stepwise multiple regression analysis the independent predictors of cICAM-1 concentration were chosen in the following order: total bilirubin; aspartate aminotransferase; cholinesterase; alpha-1-antitrypsin; and immunoglobulins. Thus, in addition to inflammation, cholestasis and decline of functioning hepatic mass may influence cICAM-1 concentration.
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PMID:Circulating intercellular adhesion molecule-1 (cICAM-1) concentration in liver disease. Relationship with cholestasis and functioning hepatic mass. 794 24

Alpha-1-antitrypsin deficiency is a common autosomal recessive disorder associated with premature development of emphysema, liver cirrhosis and hepatocellular carcinoma. This article reviews the existing literature on alpha-1-antitrypsin deficiency, with an emphasis on recent developments. A description of the protein, gene structure and function of alpha-1-antitrypsin as well as clinical aspects are presented. Treatment issues are addressed and a framework for the diagnostic workup and management of patients with alpha-1-antitrypsin deficiency and chronic liver disease is provided.
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PMID:Alpha-1-antitrypsin deficiency and liver disease. 798 61

Human peripheral blood monocytes isolated by centrifugation with Mono-Poly resolving medium, and human alveolar macrophages obtained by lung lavage during fiberoscopic bronchoscopy, were cultured in RPMI containing 2% foetal calf serum. The cultures were exposed to modified human proteins: alpha-1-antitrypsin cleaved with papain, fibrinogen degradation products (fraction D) purified from plasmin digest, and non-enzymatically glycosylated (glycated) serum albumin. Conditioned macrophage media were tested for the contents of acute phase cytokines by bioassay with hepatoma cells, and the concentration of interleukin-6 was determined with ELISA. Modified proteins stimulated macrophages to produce acute phase cytokines and the response was not abrogated by polymyxin B in distinction to stimulation of macrophages by endotoxin. Our data indicate that some proteolytically damaged proteins or the end glycosylation products formed in pathological states (acute inflammation, diabetes) may be responsible for the appearance of cytokines in the circulation.
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PMID:Origin of circulating acute phase cytokines: modified proteins may trigger IL-6 production by macrophages. Preliminary report. 804 10

The histogenesis of the undifferentiated (embryonal) sarcoma of the liver has been much debated. Originally, some investigators suggested that the tumor could originate from a mesenchymal hamartoma. Others doubted this hypothesis. The demonstration of alpha-1-antitrypsin in some tumors and of cytokeratins in others gave rise to new theories suggesting that the tumor was either a fibrous histiocytoma or a sarcomatoid hepatocellular carcinoma. As a new development in this search for the genesis of the undifferentiated (embryonal) sarcoma of the liver, this report describes a case that seems to substantiate, for the first time, the original hypothesis histogenetically linking the undifferentiated (embryonal) sarcoma and the mesenchymal hamartoma. The case is that of a 12-yr-old girl who developed an undifferentiated (embryonal) sarcoma of the liver in conjunction with a mesenchymal hamartoma. Furthermore, in places, the tumor exhibited striking epithelial differentiation as well as immunoreactivity for cytokeratins, alpha-1-antitrypsin and vimentin. Immunoreactivity for alpha-fetoprotein was limited to the areas of epithelial differentiation.
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PMID:Undifferentiated (embryonal) sarcoma arising in conjunction with mesenchymal hamartoma of the liver. 806 77

Large cell liver cell dysplasia (LCD), a suggested preneoplastic change progressing to hepatocellular carcinoma, has been reported associated with alpha-1-antitrypsin deficiency which in some countries has an increased frequency of hepatocellular carcinoma. We examined the nonneoplastic liver from 13 alpha-1-antitrypsin deficiency patients for LCD and, using a labeled streptavidin-biotin technique, for immunohistochemical markers: AAT (1/200), hepatitis B surface (HBsAg, prediluted) and core (HBcAg, 1/400) antigens, and monoclonal (1/20) and polyclonal (1/40) mutant p53, a tumor suppressor gene. There were eight males and five females ranging from 2 mo to 76 yr (mean 40 yr). Nine livers showed cirrhosis, one chronic persistent hepatitis, one portal fibrosis, and two cholestatic hepatitis (in the two infants). The nine cases with LCD included five males and four females of mean age 46 yr (range, 17-71), eight with cirrhosis and one with portal fibrosis. Only one liver with LCD and cirrhosis had HBcAg in cirrhotic and dysplastic cells. No patient had developed hepatocellular carcinoma. All 13 livers were immunonegative for HBsAg and mutant p53, and immunopositive for AAT present in normal, cirrhotic, and dysplastic liver cells. Thus, LCD was identified in 82% of adult alpha-1-antitrypsin deficiency livers (69% including infantile patients), 89% with cirrhosis, and none with malignancy. HB expression was rarely present; serology for HB and/or hepatitis C was positive in 46% adults. Immunoreactive AAT was present in dysplastic cells. p53 gene mutations do not appear to have a role in the pathogenesis of LCD in alpha-1-antitrypsin deficiency.
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PMID:Liver cell dysplasia in alpha-1-antitrypsin deficiency. 815 50

Proliferation of preexisting bile ducts, ductular metaplasia of hepatocytes and proliferation and differentiation of liver stem cells are discussed in the pathogenesis of neoductular structures in the liver. Under the condition of experimental bile duct obstruction and in extrahepatic bile duct stenosis neoductular structures are first the result of proliferation and sprouting of preexisting ducts and cholangioles. Especially in later stages of cholestasis but also in other chronic progredient liver diseases such as chronic alcoholic liver disease and chronic active hepatitis periportal hepatocytes may show a phenotypic shift towards ductular epithelia. In postnatal liver diseases hepatocytes first express keratin 7 and later keratin 19 during ductular transdifferentiation. This is in contrast to embryonal cholangiogenesis. In alpha-1-antitrypsin-deficiency, hemochromatosis, Wilson's disease, and chronic active hepatitis B cellular deposites typically located in hepatocytes such as alpha-1-AT, siderin, copper, HBs-Ag, and HBc-Ag can also be found in neoductular cells close to hepatocytes. These deposites seem to be retained during the ductular transdifferentiation of hepatocytes. Expression of bile duct-type integrin subtypes and TGF beta 1 in neoductular cells are involved in the changing parenchymal/mesenchymal interplay during neoductogenesis, resulting in periductular basal membrane and periductular fibrosis. In FNH the ductular transdifferentiation of hepatocytes is integrated in the histogenesis of micronodules and portal tract equivalents of these tumor-like lesions. Ductular structures in hepatoblastomas and especially in combined hepatocellular and cholangiocarcinomas (CHCC) may reflect the common embryologic derivation of hepatocytes and biliary epithelia. Non-neoplastic liver tissue in resection specimens of our CHCC showed a lower rate of cirrhosis, and a significantly higher Ki 67-LI of neoductular cells compared to liver tissue in resection specimens of HCC and liver metastases. 3 of 10 CHCC had developed in alpha-1-AT-deficiency, in which this protease-inhibitor was predominantly retained in periportal hepatocytes. These findings in non-neoplastic tumor-bearing liver tissue suggest that CHCC include a special histogenic type of primary liver carcinoma which in analogy to some experimental liver tumors might develop from periportal parenchymal cells.
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PMID:[Hepatic neoductules]. 860 Jun 93

The role of the hepatitis B virus (HBV) X protein in liver tumorigenesis is unresolved. Transgenic mice harboring the X gene (nt 1376-1840 under the control of the human alpha-1-antitrypsin regulatory elements) (ATX mice) display only minor histopathologic alterations of the liver. To determine if ATX mice are more susceptible to the effects of hepatocarcinogens, 12- to 15-d-old male ATX and control littermate mice were injected with a single dose (2 microgram/g body weight) of diethylnitrosamine (DEN). The animals were killed 6-10 mo after exposure and were analyzed for histological changes in the liver. One hundred percent of the DEN-treated AXT mice developed abnormal liver lesions. Then their liver tissues were compared by stereological analysis with those of non-transgenic animals, the ATX mice had a relative twofold increase in the total number of focal lesion and a twofold increase in the incidence of hepatocellular carcinoma. Elevated levels of X protein and p53 protein were not detected in carcinogen-induced nodules or tumors. These results are consistent with a model in which the expression of the HBV X protein potentiates the induction of DEN-mediated liver disease.
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PMID:Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene. 863 84

To evaluate serum alpha-1-antitrypsin (A1AT) as a prognostic factor in hepatocellular carcinoma, we studied 75 consecutive patients (60 male, 15 female, mean age +/- SD 63.0 +/- 9.3 years) in whom hepatocellular carcinoma developed with pre-existing cirrhosis. Median survival time was 245 days (range 4-1568+). 30 patients had serum A1AT concentration of < or = 2.20 g/l (Group A) while 45 (Group B) had alpha-1-antitrypsin > 2.20 g/l. Median survival was 518 days in Group A and 81 days in Group B (Mantel-Cox 20.95, P < 0.0001; hazard ratio 0.26, 95% confidence limits 0.15-0.46). By stepwise survival analysis, alpha-1-antitrypsin together with bilirubin, tumour size and blood urea nitrogen were chosen among 17 variables as the only independent predictors of survival. We conclude that measurement of serum A1AT concentration might be useful as an inexpensive, widely available prognostic marker of hepatocellular carcinoma.
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PMID:Prognostic value of serum alpha-1-antitrypsin in hepatocellular carcinoma. 866 31

Previously, we developed a model for high incidence, endogenously generated hepatocellular carcinoma (HCC), the human alpha-1-antitrypsin (alpha1AT) Z gene transgenic mouse (Z#2). We now examine the potential utility of a model for endogenous carcinogenesis utilizing the Z#2 mouse also transgenic for the lacI gene, a convenient target for in vivo mutagenesis studies. We crossed the Z#2 line and mice transgenic for lambda/lacI shuttle vector (Big Blue), for determination of lacI mutant frequency during initiation of endogenous carcinogenesis. Five month old double transgenic mice (Z#2+/lacI+) successfully displayed: (1) the expected post-inflammatory stage of Z#2 carcinogenesis; and (2) hepatic lacI mutants measured at frequencies (10(-5)-10(-4)) useful to mutagenesis studies. In this study, hepatic lacI mutation frequencies in Z#2 transgenic mice appeared to be only slightly increased (< 2x) when compared to age matched negative controls. In the future, it may be important to reconcile possibly limited lacI mutagenesis at the time of initiation and demonstrated high incidence of hepatocarcinogenesis.
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PMID:Hepatocarcinogenesis (Z#2)/mutagenesis during initiation stage. 962 74


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