p53 codon 249ser mutations in hepatocellular carcinoma patients with low aflatoxin exposure.
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Biomedical subjects
Publications and source records attributed to P J Scheuer.
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To determine the histologic pattern of hepatitis C, 54 liver biopsy specimens from 45 patients with a clinicopathological diagnosis of hepatitis C were studied. All patients were seropositive for antibody to hepatitis C virus by second-generation testing. Both transfusion-related and sporadic cases were included. More than half the samples showed chronic hepatitis without cirrhosis, whereas 44% showed developing or fully established cirrhosis. A histological pattern of mild chronic hepatitis with portal lymphoid follicles and varying degrees of lobular activity was found in many of the patients. Lymphoid aggregates or follicles were seen in 78% of biopsy specimens, but aggregates, less prominent than in hepatitis C, were also seen in 14 of 27 samples (52%) from patients with hepatitis B. We conclude that a characteristic histological pattern exists in chronic hepatitis C, that this pattern is not always found and that prominent lymphoid follicles, though not unique to hepatitis C, provide a useful diagnostic clue.
The changing pattern of innervation in the human transplanted liver was studied from the day of transplantation to 5 years later. Seven liver biopsies from non-transplant controls, 37 liver biopsies from 22 transplant patients, and one of these biopsied livers removed at retransplantation, were available for the study. Sections were immunostained for protein gene product 9.5 (PGP 9.5), neurone-specific enolase (NSE), S-100 protein, and vasoactive intestinal polypeptide. NSE and PGP 9.5 demonstrated nerves most successfully in our tissues. Staining for most small nerves was reduced by day 5 post-transplantation. Scanty fine nerves could be detected from day 13 to day 241 in occasional biopsies. Consistently identifiable immunostaining of PGP 9.5 and NSE nerve fibres was again apparent in portal areas after this time in all but one case. The findings indicate that in transplanted liver limited reinnervation can eventually take place. This could be due to either proliferation of intrinsic nerves, or regrowth of extrinsic nerves, or both.
Mast cells are known to be present in normal liver tissue but the data on their association with diseases of the liver are limited. In this study we used a long toluidine blue technique to investigate the mast cell numbers in 20 normal and 45 diseased liver biopsies containing granulomas (20 tuberculosis, 14 sarcoidosis, 4 schistosomiasis, 4 neoplasia-associated, 3 drug idiosyncrasy). Our results show that the mast cells are regular constituents of normal portal tracts and the amount of mast cells in the diseased samples corresponds to the area occupied by non-parenchymal tissues. As compared to normal controls, significantly less mast cells were present in biopsies from tuberculosis patients (p less than 0.025). Highest numbers were found in the schistosomiasis group. No link between the mast cell numbers and the cause of the granulomas could be demonstrated.
We studied the blood vessels in routinely formalin-fixed and paraffin-processed tissue from 18 hepatocellular carcinomas, three "small" hepatocellular carcinomas, and 15 benign nodular lesions representing a spectrum of conditions with which liver cell carcinomas may be confused. These were stained for a basement membrane component (collagen IV) and endothelial markers (Factor VIII-related antigen, Ulex europaeus lectin binding, and QBEnd10). The staining pattern of normal and cirrhotic liver was also examined in tissue removed with these tumours. There was an increased expression by small blood vessels for collagen IV in carcinomas and benign lesions compared with cirrhotic nodules. All endothelial markers (Factor VIII-related antigen, QBEnd10, and Ulex europaeus binding) were best expressed in liver cell carcinomas. These differences were of degree and pattern, and no single marker distinguished benign from malignant lesions. The differences in staining pattern taken together with other clinical and pathological information should be useful in diagnosis particularly of small liver cell carcinoma. The differences between benign and malignant lesions support the idea that malignant neoplastic blood vessels in the liver are of a different basic biological type from normal hepatic sinusoids, and this difference could be exploited further in future therapy.
Thirty primary liver neoplasms (16 hepatocellular, nine biliary, and five epithelioid haemangioendotheliomas) were studied for the expression of the general 'neuroendocrine' markers, neurone specific enolase (NSE) and protein gene product 9.5 (PGP 9.5). Grimelius silver staining for neurosecretory granules and immunostaining for S100 protein, HMB-45, vasoactive intestinal polypeptide (VIP), and calcitonin were also performed. Eleven of the 16 hepatocellular carcinomas stained positively for PGP 9.5, four for NSE, six for HMB-45, and two for S100 protein. Seven exhibited granular staining by the Grimelius method; eight showed immunostaining for VIP, and two for calcitonin. Three of the five haemangioendotheliomas demonstrated positive immunostaining for PGP 9.5, and two for NSE; of the nine biliary carcinomas, two showed staining for PGP 9.5 and NSE, and four contained cells staining with the Grimelius technique. Primary neoplasms of liver may show 'neuroendocrine' differentiation and this aspect of their phenotypic expression has to be considered before predicting the site of origin of a tumour in the liver.
Phenotypic expression of macrophages was studied immunocytochemically in 25 human fetal livers at various stages of development and in 20 normal human adult livers. A panel of commercially available polyclonal and monoclonal antibodies (KP1, Mac387, LN3, CR3/43, and antibodies against muramidase, alpha-1-antitrypsin, and factor XIIIa) was applied to paraffin sections. From the seventh week of gestation macrophages in the fetal liver showed differences in distribution with the various antibodies. Macrophages in adult liver similarly varied in morphology and phenotypic expression. In the light of these results, we conclude that the population of human liver macrophages is heterogeneous from an early stage of fetal development and that this heterogeneity extends into adult life.
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The histopathological features of orthotopic liver grafts were studied in 107 serial specimens from 25 patients, to assess the prevalence, possible pathogenesis and prognostic implications of hepatocellular ballooning. Ballooned hepatocytes were found in 46 (54%) of 85 biopsies taken five or more days after transplantation from 16 patients. They were not found in any of the protocol biopsies taken at the time of the operation. Ballooning usually appeared in the second week after transplantation, and in most patients persisted to the time of the latest biopsy studied. The affected cells were always found in acinar zone 3, and sometimes also in other zones. Forty-four of the 46 biopsies with ballooning were taken during a period of clinical and biochemical cholestasis. In 13 of the 16 patients the degree of ballooning paralleled the severity of the cholestasis. Electronmicroscopy of affected hepatocytes showed conspicuous dilatation of the cisternae of the rough endoplasmic reticulum rather than the classical features of cholestasis. It was therefore concluded that ballooning was associated with but not directly caused by bile retention. There was no obvious association between ballooning and cellular rejection, sepsis, immunosuppressive therapy or parenteral nutrition. The most severe early ballooning was associated with serum transaminase levels over 1000 IU/l within 48 h of transplantation, suggesting that ischaemia was one of the pathogenetic factors. Hepatocellular ballooning did not in itself appear to have sinister short-term prognostic implications.
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The sinusoids of 30 human hepatocellular carcinomas of various types were examined by electron microscopy and histochemically for binding to the Ulex europaeus lectin (UEA1). A population of sinusoidal macrophages was identified with an antibody to lysozyme (muramidase). The UEA1 binding was negative in normal sinusoids but positive in the tumor vessels. Macrophages resembling Kupffer cells were found within the tumor vessels but in smaller numbers than in either normal or cirrhotic liver tissue. Fibrolamellar and sclerosing carcinomas contained the smallest numbers. Ultrastructurally, endothelial cells of tumor vessels were thicker than normal, with fewer fenestrations. They contained bundles of microfilaments and showed basement membrane formation. Subendothelial myoid cells were found. These findings indicate that the sinusoidal vessels of hepatocellular carcinomas show features of true capillaries and precapillary blood vessels. The degree of this difference from normal hepatic sinusoids may reflect the relative immaturity of the cancer cells.
Analysis of secondary metabolites derived from marine organisms has revealed a broad spectrum of novel molecular architecture. The function of these compounds in their natural habitat is linked to various aspects of species survival, and the compounds have also served as characteristic chemical markers through successive trophic levels. Fundamental questions concerning the locus of synthesis in complex and intricate assemblies of plants and animals and the pathways of biosynthesis are beginning to be answered. It is now apparent that the marine environment gives rise to some distinctive chemistry, which is generated along characteristic pathways. Some of the newly described compounds have already become valuable tools in biomedicine.
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Eighteen red-bellied tamarins (Saguinus labiatus), experimentally infected with hepatitis A virus (HAV), were followed for up to 1.5 years after initial challenge. Half of these animals developed protracted alanine aminotransferase (ALT) abnormalities, which lasted for between 23 and 55 weeks post-challenge. IgM anti-HAV was detected intermittently during the early phase of their relapsing hepatitis and never after return of ALT levels to normal. The possibility that these findings may be related to continued HAV replication, coinfection with another agent, or the result of an autoimmune phenomenon triggered by HAV are discussed.
Ulex europaeus 1 lectin (UEA1) has previously been shown to bind to hepatic sinusoidal endothelium in cirrhotic liver. This study was undertaken to determine the relationship between UEA1 sinusoidal binding and hepatic venous pressure gradient in patients with portal hypertension. Twenty one liver specimens (including 18 from patients with alcoholic cirrhosis) biopsied within an interval of 1 month from the hepatic venous pressure study were examined for UEA1 binding. The consistent staining pattern of normal liver controls formed the basis for the criteria of positivity and grading system. Seventeen cases (81%) were positive, but the staining intensity or extent showed no strong correlation with the hepatic venous pressure gradient; however, three of the four negative cases were in the low pressure range which is rarely associated with variceal bleeding. We conclude that UEA1 is a useful marker for significant sinusoidal alterations in portal hypertension and a helpful adjunct in the histological diagnosis of cirrhosis.
Various anatomical factors were examined which might provide passive resistance to portal venous flow and so cause portal hypertension. Methods included the measurement of portal pressure (WHVPG) in cirrhotic and non-cirrhotic patients, morphological assessment by semiquantitative grading of severity of disease, calculation of hepatocyte size indices, and assessment of volume density of hepatocytes, sinusoids, Disse's space and Disse's space collagen by electron microscopy. The wedged hepatic venous pressure gradient increased with progression of disease and portal hypertension was present before histologically detectable cirrhosis had developed. With increasing progression of disease towards cirrhosis, the relationship between individual and aggregated features and the WHVPG diminished and lost statistical significance. Hepatocyte size increased with progression of histological changes and correlated significantly with increase of WHVPG, both in non-alcoholic and alcoholic patients. Disse's space collagen was increased significantly in non-alcoholic chronic active hepatitis compared with patients with near-normal liver. No significant decrease of sinusoidal space was found. Multiple factors rather than any single feature influence the development of portal hypertension.
A case of severe acute hepatitis caused by cyproterone acetate in a 71 year old man with prostatic carcinoma is reported with a review of the literature on hepatic reactions to this drug. The association between the use of cyproterone acetate and liver abnormalities is poorly documented. This is the fourth published report of adverse hepatic reaction to cyproterone acetate and it substantiates other evidence that cyproterone acetate is potentially hepatotoxic. Monitoring of liver function tests should be mandatory in patients receiving high doses of cyproterone acetate; the drug should be withdrawn immediately if abnormal liver function tests are found.