Hepatology

doi: 10.1002/hep.1840090301pmid: N/A

McClain, Craig J.; Cohen, Donald A.

doi: 10.1002/hep.1840090302pmid: 2920991

Tumor necrosis factor is a cytokine that mediates many of the biologic actions of endotoxin. Recent studies have shown that tumor necrosis factor administration may cause liver injury and that tumor necrosis factor may mediate the lethality of the hepatotoxin galactosamine. One of the most potent inducers of tumor necrosis factor production is endotoxin. Because patients with alcoholic liver disease frequently have endotoxemia and because many of the clinical manifestations of alcoholic hepatitis are known biologic actions of tumor necrosis factor, we thought it would be important to evaluate tumor necrosis factor activity in patients with alcoholic hepatitis. Basal and lipopolysaccharide‐stimulated tumor necrosis factor release from peripheral blood monocytes, a major source of tumor necrosis factor production, was determined in 16 patients with alcoholic hepatitis and 16 healthy volunteers. Eight of 16 alcoholic hepatitis patients and only two of 16 healthy volunteers had detectable spontaneous tumor necrosis factor activity (p < 0.05). After lipopolysaccharide stimulation, mean monocyte tumor necrosis factor release from alcoholic hepatitis patients was significantly increased to over twice that of healthy controls (25.3 ± 3.7 vs. 10.9 ± 2.4 units per ml, p < 0.005). We conclude that monocytes from alcoholic hepatitis patients have significantly increased spontaneous and lipopolysaccharide‐stimulated tumor necrosis factor release compared to monocytes from healthy volunteers. We suggest that some of the metabolic abnormalities and possibly some of the liver injury of alcoholic hepatitis may be due to enhanced tumor necrosis factor production.

Chen, Wan; Gendrault, Jean‐Louis; Steffan, Anne‐Marie; Jeandidier, Eric; Kirn, André

doi: 10.1002/hep.1840090303pmid: 2465986

Fat‐storing cells were isolated from 15‐day‐old mouse sinusoidal cell cultures (Kupffer or endothelial cells), where they had multiplied abundantly; they were then purified by a negative selection method based on the fact that they do not possess Fc receptors, as do both other types of cells.

Yang, Sien‐Sing; Korula, Jacob; Sundheimer, James E.; Keyser, Anthony J.

doi: 10.1002/hep.1840090304pmid: 2920992

Digoxin‐like immunoreactive substances, which cross‐react with digoxin antibody, have been found to have natriuretic effect and Na+,K+‐ATPase inhibitory effect. The role of digoxin‐like immunoreactive substances in chronic liver disease was studied by radioimmunoassay in 63 serum and 60 urine samples from 58 patients with chronic liver disease and compared with 16 controls. Although the mean serum digoxin‐like immunoreactive substances level of compensated chronic liver disease patients (0.06 ± 0.05 ng per ml, p < 0.01) was higher than that of controls (0.02 ± 0.03 ng per ml), only four patients had serum digoxin‐like immunoreactive substances higher than 0.10 ng per ml. Mean serum digoxin‐like immunoreactive substances level was much higher in patients with decompensated chronic liver disease who had ascites (0.32 ± 0.17 ng per ml, p < 0.001), hepatorenal syndrome (0.57 ± 0.20 ng per ml, p < 0.001) and hepatic encephalopathy (0.43 ± 0.20 ng per ml, p < 0.001). Five patients with recent variceal hemorrhage requiring transfusions and saline infusion had significantly increased serum digoxin‐like immunoreactive substances (mean: 0.16 ± 0.06 ng per ml, p < 0.001) before the development of clinically detectable ascites. The serum digoxin‐like immunoreactive substances level was positively correlated with serum total bilirubin (r = 0.581, p < 0.001), AST (r = 0.454, p < 0.001), serum creatinine (r = 0.539, p < 0.001), urine digoxin‐like immunoreactive substances (ng of urine digoxin‐like immunoreactive substances per gm of urine creatinine, r = 0.578, p < 0.001) and negatively correlated with serum albumin (r=−0.604, p < 0.001), prothrombin activity (r=−0.589, p < 0.001), serum sodium (r=−0.685, p < 0.001) and urine sodium (mEq of urine sodium per gm of urine creatinine; r=−0.476, p < 0.001). The present study shows increased serum digoxin‐like immunoreactive substances in decompensated chronic liver disease. The negative correlation between serum digoxin‐like immunoreactive substances and urine sodium suggests that digoxin‐like immunoreactive substances level is higher in patients having low urinary sodium output. This finding may be explained by a possible renal insensitivity to digoxin‐like immunoreactive substances in decompensated chronic liver disease.

Moorman, Antoon F. M.; Vermeulen, Jacqueline L. M.; Charles, Robert; Lamers, Wouter H.

doi: 10.1002/hep.1840090305pmid: 2563984

Immunohistochemical analysis of human liver (8 to 94 years) shows a compartmentation of ammonia‐metabolizing enzymes across the acinus. The highest concentration of carbamoylphosphate synthetase (ammonia) is found in the parenchymal cells around the terminal portal venules. Glutamine synthetase is found in a small pericentral compartment two to three cells thick. In contrast to observations in rat liver, in human liver a well‐recognizable intermediate zone can be distinguished in which neither enzyme can be detected. This intermediate zone is not yet established at the age of 8 years but can be recognized in livers from 25 years onward.

Snodgrass, Philip J.

doi: 10.1002/hep.1840090306pmid: 2920993

We produced moderately severe, inactive micronodular cirrhosis in rats using CCl4 and measured the urea cycle enzyme activities in liver after feeding a 15% casein diet for 1 week and again after a 60% casein diet for 1 week. There was no deficiency of any of the five urea cycle enzymes in cirrhotic livers of rats pair‐fed the 15% casein diet. Argininosuccinate synthetase and carbamyl phosphate synthetase activities were lower than in non‐pair‐fed controls by some baselines. All five enzymes in cirrhotic livers were induced 1.5‐ to 3‐fold by the high‐protein diet expressed as units per 100 gm of rat. The level of carbamyl phosphate synthetase activity was lower in the livers of rats pair‐fed the 60% casein diet than in control livers based on wet weight, collagen‐free protein and DNA, but the activities were equal expressed as units per 100 gm of rat. This example of CCl4‐induced cirrhosis in the rat does not serve as a good model for human cirrhosis, in which the urea cycle enzymes are reported to be decreased in activity.

Renaud, Guy; Hamilton, Robert L.; Havel, Richard J.

doi: 10.1002/hep.1840090307pmid: 2920994

Rats were treated with 17α‐ethinyl estradiol to induce high levels of low‐density lipoprotein receptors in hepatocytes. When these rats were given intravenous injections of low‐density lipoprotein‐colloidal gold complexes, most of the gold (labeled with 195Au) appeared to be taken up by Kupffer cells, as were complexes of colloidal gold with albumin or polyvinylpyrrolidone. However, when these rats were also administered gadolinium chloride, which blocks Kupffer cell activity, most of the low‐density lipoprotein‐gold (but not gold complexed with albumin or polyvinylpyrrolidone) was taken up into hepatocytes by receptor‐mediated endocytosis and concentrated in peribiliary lysosomes, as determined by electron microscopy. Colloidal gold taken up as a complex with low‐density lipoprotein was excreted into the feces via the common bile duct at a maximal rate of about 5% daily, 4 to 12 days after injection. Thereafter, the rate of gold excretion fell off until reaching a plateau after 3 weeks. At this late time, most of the colloidal gold was shown by electron microscopy to be in Kupffer cells, whereas earlier (6 days after injection) it was contained mainly in older hepatocytic lysosomes, identified by lipofuscin granules. It is concluded that, in rats, hepatocytic lysosomes empty most of their contents into bile every week or two, apparently by exocytosis.

Whitington, Peter F.; Kehrer, Beat H.; Whitington, Susan H.; Shneider, Benjamin; Black, Dennis D.

doi: 10.1002/hep.1840090308pmid: 2920995

A major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux‐en‐Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague‐Dawley rats.

Bacon, Bruce R.; Britton, Robert S.; O'Neill, Rosemary

doi: 10.1002/hep.1840090309pmid: 2920996

Peroxidative decomposition of organelle membrane phospholipids with subsequent organelle dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. We studied the effects of different α‐tocopherol concentrations on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. There was no evidence of mitochondrial lipid peroxidation (conjugated dienes) or alteration in mitochondrial oxidative metabolism in α‐tocopherol‐deficient rats with normal hepatic iron levels. Significant reductions in mitochondrial respiratory control ratios and oxidative phosphorylation ratios were seen in association with increased conjugated dienes in all three groups of iron‐loaded rats regardless of the α‐tocopherol status (deficient, normal or excess); thus, the α‐tocopherol deficiency associated with dietary iron overload in this experimental model is not responsible for the mitochondrial abnormalities observed. In addition, chronic parenteral administration of α‐tocopherol to iron‐loaded animals, which increased hepatic levels of this substance 3‐fold, did not ameliorate the hepatic mitochondrial lipid peroxidation or the defects in mitochondrial oxidative metabolism resulting from iron overload.

Katsumoto, Fujio; Miyazaki, Kohji; Nakayama, Fumio

doi: 10.1002/hep.1840090310pmid: 2920997

The role of Kupffer cells during reparative regeneration of rat liver was investigated with an in vitro experimental model. Conditioned media from primary cultures of Kupffer cells isolated from intact and regenerating liver were added to primary cultures of hepatocytes, and [3H]thymidine incorporation into DNA was studied. Kupffer cell‐conditioned media from intact liver and regenerating remnant liver significantly stimulated DNA synthesis in hepatocytes as compared with control media (p<0.05). Moreover, the stimulating activity of Kupffer cells prepared from regenerating liver at 6 and 12 hr after partial hepatectomy was significantly higher than that of Kupffer cells from untreated rats (p<0.05). The activity was found in serum‐free conditioned media. This stimulating activity exponentially increased as the increase of the number of the cultured cells, indicating that the stimulating activity was released directly by cultured Kupffer cells. These results suggest that Kupffer cells stimulate DNA synthesis in hepatocytes by producing and releasing certain factor(s) at an early stage of liver regeneration after partial hepatectomy.