Nonparenchymal Cells Cultivated from Explants of Fibrotic Liver Resemble Endothelial and Smooth Muscle Cells from Blood Vessel WallsVoss, Bruno; Rauterberg, Jürgen; Pott, Gerhard; Brehmer, Ute; Allam, Salah; Lehmann, Rolf; Bassewitz, Dirk B. V.
doi: 10.1002/hep.1840020105pmid: 7033099
Tissue specimens from human fibrotic liver obtained by needle biopsy were cultured. Two cell types emerged from the tissue explants. From their morphology and biosynthetic products they resembled smooth muscle cells and endothelial cells from blood vessel walls. In the “endothelial” cells, factor VIII‐associated protein was demonstrated by indirect immunofluorescence. Synthesis of collagen types I and III, basement membrane collagen types IV and V, and fibronectin by both cell types was observed by immunofluorescence microscopy. Homogeneous cultures of “smooth muscle cells” were observed in subcultures. After incubation with (14C)glycine, collagen was isolated and characterized by CM cellulose chromatography, and consisted mainly of types I and III. These data suggest involvement of mesenchymal cells in hepatic fibrosis; they presumably originate from blood vessel or sinusoidal walls.
Drugs as Indicators of Hepatic FunctionBranch, Robert A.
doi: 10.1002/hep.1840020115pmid: 7054072
It is well recognized that liver disease may influence the disposition of many drugs. Conversely, it has been suggested that knowledge of the disposition of a model drug might provide an index of certain aspects of hepatic function. This review discusses the physiology of drug disposition and indicates how recent progress in understanding the determinants of drug disposition has provided useful indices of individual aspects of hepatic function. Topics which are discussed are the interpretation of pharmacokinetic parameters as indices of hepatic function, including half–life clearance, and intrinsic clearance. Utilizing the “intact hepatocyte hypothesis” as an operational model, an approach is described that uses the pharmacokinetic disposition of high and low intrinsic clearance drugs following p.o. and i.v. administration to provide quantitative estimates of hepatic function, flow to functioning hepatocytes, and the extent of portasystemic shunting through the liver. Thus, the theoretical basis for quantitation of certain aspects of hepatic function are available. It remains to be determined whether these indices will provide clinically useful measures to follow the natural history of hepatic disease.
Morphologic Study of Intermediate Filaments in Rat HepatocytesFrench, Samuel W.; Kondo, Isao; Irie, Tetsuya; Ihrig, Thomas J.; Benson, Nancy; Munn, Robert
doi: 10.1002/hep.1840020106pmid: 7198614
Rat livers perfused with 0.5% Triton X‐100 for 15 to 90 min followed by 1% sodium dodecyl sulfate for 30 min were studied by electron microscopy and polyaerylamide gel electrophoresis. After 15 min of perfusion, a rich network of intermediate filaments and microtubules was visualized in the cytoplasm of hepatocytes. Using stereopairs, branching was visualized. Connections of filaments were noted with nuclei, centrioles, microtubules, vesicles, and rough endoplasmic reticulum. The existence of connections supported the concept that intermediate filaments may function to integrate mechanically the cytoplasmic space as postulated by Lazarides.
Thyroxine Binding Globulin and Thyroid Function Tests in Patients with Hepatocellular CarcinomaKalk, W. John; Kew, Michael C.; Danilewitz, Mervyn D.; Jacks, Frederick; Van Der Walt, L. Andre; Levin, Joseph
doi: 10.1002/hep.1840020112pmid: 6274780
To determine the prevalence of elevated serum concentrations of thyroxine binding globulin (TBG) in patients with hepatocellular carcinoma (HCC) and the influence of the associated cirrhosis, TBG was measured in 39 patients with HCC, 22 with and 17 without cirrhosis, in 20 patients with cryptogenic macronodular cirrhosis but without HCC, and in 40 matched controls. The mean serum TBG concentration in the patients was 34.5 ± 17.7 μg per ml, compared to 21.4 ± 6.8 μg per ml in controls and 20.5 ± 6.3 μg per ml in cirrhosis without HCC (p < 0.01). The presence or absence of cirrhosis in the HCC patients did not significantly influence the frequency with which elevated TBG levels were found; levels were normal in every subject with cirrhosis and no HCC. The mean thyroxine (T4): TBG ratio was 5.58 ± 1.78 in controls and was reduced in HCC patients with both elevated (3.33 ± 0.80, p < 0.001) and normal TBG values (4.39 ± 1.90, p < 0.05), and in cirrhotics without HCC (4.29 ± 1.01, p < 0.01). T4 and TBG concentrations correlated significantly in controls, in HCC patients with elevated TBG, and in the cirrhotics without HCC. It is concluded that in patients with HCC (i) TBG levels may be elevated both in the presence or absence of cirrhosis; (ii) there is reduced binding of T4 TBG, and (iii) a low T4:TBG ratio excludes the diagnosis of hyperthyroidism in the presence of high T4 levels. TBG levels are normal in patients with cryptogenic macronodular cirrhosis without HCC.
Collagen Production by Rat Hepatocytes and Sinusoidal Cells in Primary Monolayer CultureTseng, Scheffer C. G.; Lee, Philip C.; Ells, Peter F.; Bissell, D. Montgomery; Smuckler, Edward A.; Stern, Robert
doi: 10.1002/hep.1840020104pmid: 7054066
The cellular sources of collagen in normal rat liver have been examined. Hepatocytes and nonparenchymal (sinusoidal) cells were isolated and established in primary monolayer culture. These cells were incubated with radiolabeled proline in the presence of L‐ascorbate and β‐amino‐propionitrile. Nondialyzable material was prepared from the cell layer and the medium from each type of culture. The level of collagen accumulation was determined by measuring labeled hydroxyproline and sensitivity to purified bacterial collagenase. In hepatocytes, collagen represented 0.2% of both secreted and cell‐associated labeled protein. In sinusoidal cells, collagen was 3.2% of secreted and 1.1% of cell‐associated proteins. The total secreted labeled collagen, expressed per microgram of DNA, was similar in hepatocytes and sinusoidal cells. However cell‐associated collagen in hepatocyte culture was approximately 10‐fold that present in sinusoidal cells. These findings indicate that, while collagen formation is a relatively important function of sinusoidal cells, in normal liver the contribution of hepatocytes to total hepatic collagen accumulation may be substantial.