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- The present study is concerned with changes in the number and localization of S-phase cells in the liver of rats exposed to dimethylnitrosamine (DMN). S-phase cells were detected by immunohistochemistry after injection of bromodeoxyuridine (BrdU) and exposure of paraffin sections of liver tissue to the antibody anti-BrdU. With respect to controls, the number of S-phase cells increased four to fivefold in DMN-treated animals in the first week of treatment and remained significantly higher thereafter, in association with the formation of septa. At all times, the labelling index was higher in littoral cells than in hepatocytes. No labelling was observed in biliary cells. This behaviour is different from that reported in other situations, for instance in regeneration after partial hepatectomy, which suggests that besides hepatocytes and littoral cells replacement, an involvement of the latter cell line in the inflammatory reaction, synthesis of extracellular matrix components and formation of septa may account for this particular pattern. [ABSTRACT FROM AUTHOR]

ABSTRACT- The aim of the present study was to determine if data on the number and acinar distribution of apoptotic bodies (AB) in normal liver could help in the understanding of cell kinetics in the liver, and the mechanism of early ethanol-induced liver damage. Normal male Sprague-Dawley rats were studied. They had free access to Purina chow and drinking water. Ethanol-treated rats received the drug at increasing concentration in drinking water for 5 weeks. The following parameters were measured: number of AB in the lobule, topographical localization, distance from terminal hepatic veins (THV), i.e. row of hepatocytes concerned, H1 being the closest to the THV. The results show that AB are rare in the normal liver and are always observed in zone 3, next to the THV. Of 149 THV examined, 56 showed one associated AB, exceptionally two. 74% of the AB were confined to the first row of hepatocytes (H1), 21% to H2, 4% to H3, and 1% to H4. In ethanol-treated rats the mean number of AB was 2 or 3 for each THV. 42% were found in H1, 32% in H2, 15% in H3, 7% in H4, and 4% in H5. The data show that AB are not randomly dispersed in normal liver but show a preferential acinar distribution. In addition, most AB are located in the row of liver cells immediately adjacent to the THV. If apoptosis is indeed an expression of physiological cell renewal, these findings support the concept that zone 3 contains older hepatocytes. In ethanol-treated animals, besides the O2 lobular gradient and increased rate of formation of intermediate metabolites, the age of pericentral hepatocytes may represent an additional risk factor in ethanol-induced liver damage. [ABSTRACT FROM AUTHOR]

ABSTRACT- Horseradish peroxidase (HRP) and lanthanum chloride (LaCl3) are useful tools for, respectively, the study of vesicular transport through the hepatocyte and the study of the permeability of junctional complexes. These tracers have been used to detect the changes associated with the choleresis independent of bile acids induced by valproic acid (VPA) in rats. The animals were given a single dose of VPA (600 mg/kg, ip). HRP (100 mg/kg) or 5 mM LaCl3 were given intraportally after 1 h, when bile flow had increased twofold. The excretion of HRP in bile was measured colorimetrically up to 2 h after HRP. Ultrastructural morphometry was conducted on liver of intact rats taken from 1 to 40 min after HRP. The volume density (VD) of HRP-containing vesicles and of HRP-containing multivesicular bodies (MVB) was counted. In VPA-treated rats, HRP appeared in bile with a peak showing at 5 min against 20 min in controls, but the total amount of HRP excreted was less than in controls. The intrahepatocytic vesicular transport of HRP was also modified, showing a peak at 3 min in VPA-treated rats compared to 10 min in controls, together with a decreased VD of pericanalicular vesicles. This was accompanied by an increase of HRP-containing MVB, already evident at 5 min. VPA-induced changes in HRP transport through the hepatocytes appeared twofold: 1) during VPA-induced stimulation of bile flow, there was an early and short-lived increase of transcellular transport and biliary elimination of HRP: 2) a diversion of HRP towards the indirect, lysosomal pathway apparently occurred, in agreement with previous findings concerning the formation of numerous cytolysomes induced by VPA ( Hepatology 1984: 4: 1159-1166). The decreased amount of HRP excreted in bile could be accounted for by a diversion of HRP towards the degradation pathway. The pattern of distribution of LaCl3 was similar in VPA-treated animals and in controls, suggesting that gross structural alterations of the junctional complexes are unlikely to occur during VPA-induced choleresis. [ABSTRACT FROM AUTHOR]

ABSTRACT- The frequency of fibrosis of the terminal hepatic venule (FTHV) has been investigated by two observers unaware of the patient's history, in needle biopsy specimens showing normal histology (n = 23), alcoholic steatosis (n = 23), steatosis in diabetes or overweight (n = 26), alcoholic hepatitis (n = 21), or virus-related chronic active hepatitis (n = 44). FTHV was coded following a scale from 0 to 3 of severity. Minimal (grade 1) FTHV was seen in most venules of biopsies with a normal histological pattern, and was considered a normal feature. Grade 2 of FTHV was absent in the group showing normal histology but was evident in 17.4% - 39.7% of the venules observed in the other groups without attaining diagnostic relevance. The percentage rate of severe (grade 3) FTHV was 0.0, 4.9, 6.6, 18.7 and 2.9 in the respective groups as delineated above. In alcoholic hepatitis, severe FTHV therefore showed a higher frequency than in virus-related chronic hepatitis (p<0.001), with high values of sensitivity (0.75), specificity (0.93), and predictivity (0.84 positive, 0.98 negative) for ethanol aetiology. The ethanol-related diagnostic value of FTHV however, was low in steatosis. [ABSTRACT FROM AUTHOR]

ABSTRACT- The study reports functional and morphological findings in eight male subjects undergoing anticonvulsant therapy for periods from 20 days up to 15 years. All subjects showed an increased activity of the hepatic microsomal NADPH cytochrome c reductase and an increased amount of smooth membranes in hepatocytes. The enzymatic activity was higher in the first years of treatment. Quantitative ultrastructural analysis showed that a twofold increase of the smooth membranes of hepatocytes had already been reached after 20 days of therapy, with a modest additional increase occurring thereafter. Both enzymatic and structural changes appear to be related to therapy. In addition, abnormal lipofuscin-related cytoplasmic formations were present in the hepatocytes of five subjects. Such formations are thought to represent an accumulation of abnormal degradation products, possibly related to an interaction of the drug(s) metabolites with cellular components. [ABSTRACT FROM AUTHOR]

Background/aims: The involvement of a direct viral cytopathic effect or an immune-mediated mechanism in the progression of hepatic damage in chronic hepatitis C is controversial. The type of immune response is itself a matter of controversy, and histological data are lacking. The aim of this study was to identify the factors associated with the progression of liver injury in 30 HCV/RNA-positive untreated patients with chronic hepatitis., Methods: Necroinflammatory and architectural damage were evaluated using Ishak's score. Activated hepatic stellate cells (HSC) were visualized by immunohistochemistry for alpha-smooth muscle actin (alphaSMA) and quantitated by morphometry. Plasma HCV/RNA was evaluated using a competitive RT-PCR method. To study the type of immune response involved in the progression of liver injury, interferon gamma (IFNgamma)-positive cells (as expression of a Th1-like response) were evaluated by immunohistochemistry and quantitated by morphometry., Results: HSC were mostly detected close to areas of lobular necroinflammation or lining fibrotic septa. The alphaSMA- and Sirius Red-positive parenchyma correlated significantly with necroinflammatory and architectural scores. IFNgamma-positive cells were detected in periportal areas associated with the inflammatory infiltrates and significantly correlated with architectural damage. No relationship was found between the histological features of liver injury and viral load., Conclusions: HSC activation and progression of liver injury are unrelated to viral load but associated with a Th1-like response, a plausible target for the treatment of chronic hepatitis C.

The expression of proliferating cell nuclear antigen (PCNA) was examined in normal human and rat liver fixed in either formaldehyde or methanol, and was compared with the incorporation of bromodeoxyuridine (BrdU) in S-phase cells. Codistribution of PCNA and BrdU was assessed in rat liver by double immunohistochemical staining using PC10 and anti-BrdU monoclonal antibodies to identify labelled nuclei of parenchymal and sinusoidal cells. In formaldehyde-fixed human biopsies (n = 13) PCNA-labelling index (PCNA LI) was 0.43 +/- 0.24% (mean +/- SEM) for hepatocytes and 0.09 +/- 0.03% for sinusoidal cells. A great interspecimen variability was observed and a preferential lobular distribution was not evident. In methanol-fixed human liver (n = 8) the immunostaining was strong. PCNA LI was 0.05 +/- 0.01% for hepatocytes and 0.14 +/- 0.01% for sinusoidal cells. 75% of labelled hepatocytes and 60% of labelled sinusoidal cells were found in acinar zone 1. In formaldehyde-fixed rat liver (n = 10) a weak nuclear staining and a great interspecimen variability were evident. LI was 0.13 +/- 0.07% for hepatocytes and 0.40 +/- 0.21% for sinusoidal cells without preferential acinar distribution. In methanol-fixed rat liver (n = 10), PCNA LI was 0.14 +/- 0.02% for hepatocytes and 0.40 +/- 0.04% for sinusoidal cells. 64% of labelled hepatocytes and 50% of labelled sinusoidal cells were found in zone 1. Only on methanol-fixed material did double immunohistochemistry show an almost complete overlap of BrdU and PCNA labelling. The PCNA LIs and the zonal distribution of labelled nuclei as obtained in methanol-fixed material are in keeping with previous reports using 3H-thymidine (3H-Thy) incorporation, suggesting that PCNA immunostaining represents a valid alternative to 3H-Thy.(ABSTRACT TRUNCATED AT 250 WORDS)