Complications of transplantation for protoporphyric liver disease.
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Female↗
Biomedical subjects
A Holstege
Publications and source records attributed to A Holstege.
High interleukin-6 concentrations in hepatic ascites.
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Ascitic Fluid↗
Effects of hypoxia on the oxygen-dependent metabolism of prostaglandins and adenosine in liver cells.
In this study, the capacity of hepatocytes to degrade prostaglandins diminished if the partial oxygen pressure dropped below 5%. This decrease was accompanied by an increased lactate/pyruvate ratio, a decrease in fatty acid oxidation and a drop in the ATP level. The degradation of exogenous adenosine increased with decreasing oxygen tension. At a partial oxygen pressure below 10%, the conversion of uric acid to allantoin, the final catabolite of adenosine in the rat, was strongly inhibited, resulting in the accumulation of uric acid in the medium. A good correlation was observed between the partial oxygen pressure, the oxidation of uric acid to allantoin and the degradation of prostaglandins D2 and E2, suggesting a peroxisomal pathway of hepatic prostaglandin oxidation. Subcellular fractionation of liver homogenates revealed peroxisomes as the site of degradation of prostaglandins D2 and E2 augmented by cytosolic components. The similarity of the degradation products found in the cell-free system, in hepatocytes and in the perfused liver further supports a peroxisomal degradation of prostaglandins in vivo. Stimulated liver macrophages (Kupffer cells) produced the same amount and pattern of eicosanoids at 1% and 21% O2. Even the formation of superoxide remained unaffected down to a partial pressure of 1%. At partial O2 pressures below 1%, the production of prostaglandins and superoxide became strongly inhibited. These results indicate that essential oxygenation reactions in activated Kupffer cells, including prostaglandin synthesis, possess high affinities to oxygen, while the peroxisomal pathway of prostaglandin oxidation in hepatocytes is sensitive to an O2 tension as low as 5%.
Adenosine↗
The role of drug treatment in variceal bleeding.
Pharmacological management of acute variceal hemorrhage appears to be effective in patients with liver cirrhosis. Somatostatin and presumably its longer-acting analog, octreotide, are more efficient and safer than other vasoconstrictors like vasopressin, terlipressin or their combination with nitroglycerin. Drug treatment, however, usually represents only a valuable adjunct to other measures to stop bleeding such as endoscopic variceal sclerotherapy. Prophylaxis of first bleeding by beta-blockade appears justified in patients at a high risk of bleeding which still has to be defined more precisely. Prevention of recurrent hemorrhage can be effective in some but not in all of the patients with liver cirrhosis and a first bleeding episode. Treatment of patients with good liver function under direct control of the wedged hepatic vein pressure gradient presumably will reduce the failure rate of prophylaxis with beta-blockade.
Esophageal and Gastric Varices↗
Acetaldehyde-modified epitopes in liver biopsy specimens of alcoholic and nonalcoholic patients: localization and association with progression of liver fibrosis.
Acetaldehyde, the first product of ethanol oxidation, has been shown to stimulate collagen gene expression and to form protein-acetaldehyde adducts. Because little is known about these adducts in human liver tissue, we assessed, with an immunohistochemical procedure, the presence and location of acetaldehyde-protein adducts in liver biopsy specimens of alcoholic patients. In addition, we correlated the presence of adducts with the progression or subsequent occurrence of liver fibrosis. The group included 106 patients with high alcohol consumption (> 90 gm ethanol/day for the last 5 yr), 10 nonalcoholic patients with normal livers and 23 patients with other liver diseases. Sixty-four of the 106 alcoholic patients had a second liver biopsy, whose specimen was used to assess the progression of liver fibrosis. Polyclonal antibodies were produced against homologous low-density lipoprotein purified from rabbit serum and modified in vitro in the presence of acetaldehyde. Protein-acetaldehyde adducts could be detected by immunohistochemistry in biopsy specimens of 90 alcoholic patients (85%), in none of the 10 nonalcoholic patients with normal livers and in 65% of the patients with nonalcoholic liver disease. Acetaldehyde-modified epitopes were detected in the intracellular and extracellular compartment. Intracellular protein-acetaldehyde adducts were localized in the cytoplasm of hepatocytes with a more intense staining in zone 3. No correlation existed between the intensity of intracellular staining and the histologically assessed severity of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaldehyde↗
Delayed spontaneous opening of a self-expanding metal stent bridging a malignant esophageal stenosis.
We report on a case of an 85-year-old man with dysphagia who suffered from a stenosing esophageal adenocarcinoma that could not be treated by surgery. The tumor demonstrated circumferential growth and extended from 14 to 22 cm from the incisors. There were no esophago-tracheal fistulas. The stenosis could be negotiated with the endoscope. Under fluoroscopic guidance, a self-expanding Strecker stent was placed in the stenosed area with no prior dilatation. After releasing the stent an x-ray revealed a twisted and wrinkled stent which had expanded to only half of its maximum diameter. The patient's symptoms had not improved. Four days later dysphagia resolved when the stent spontaneously corrected its position and was found to be maximally expanded. On the basis of this observation it may be concluded that, at least in some cases, self-correction of an initially unsatisfactory positioning of a Strecker stent may be expected, even after four days.
Adenocarcinoma↗
[Hepatobiliary diseases in Crohn disease and ulcerative colitis].
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Biliary Tract Diseases↗
Stimulation of collagen alpha 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?
We have shown that lipid peroxidation stimulates collagen alpha 1(I) gene transcription in cultured cells. Because increased lipid peroxidation and collagen production coexist in many hepatic disorders, including experimental carbon tetrachloride intoxication, we investigated whether lipid peroxidation modulates collagen gene expression in rats treated with carbon tetrachloride. In this animal model, we show colocalization of increased collagen alpha 1(I) mRNA with lipid peroxidation by means of in situ hybridization and immunohistochemical study for malondialdehyde and 4-hydroxynonenal protein adducts, respectively. However, allyl alcohol treatment, which induced a similar degree of hepatocellular injury but without aldehyde-protein adducts, did not increase collagen alpha 1(I) gene expression, suggesting that hepatocyte necrosis is not sufficient to induce the expression of collagen type I. Furthermore, in the absence of an inflammatory response, coculture experiments of hepatocytes and Ito cells treated with carbon tetrachloride indicate that hepatocytes exert a "paracrine" stimulation of both lipid peroxidation and collagen gene expression in Ito cells. These experiments suggest that hepatocyte lipid peroxidation plays a major role in the regulation of collagen alpha 1(I) gene expression by Ito cells and that it may be a link between hepatocyte injury and hepatic fibrosis.
1-Propanol↗
Excretion of caffeine and its primary degradation products into bile.
Caffeine, widely consumed in beverages, is known to alter several biliary parameters that can affect gallstone pathogenesis. To address the question whether methylxanthines can act on the luminal side of biliary epithelial cells, we measured caffeine and its primary demethylation products in human bile. Eight patients had an external biliary drainage due to bile duct or gallbladder disease. Two of the patients suffered from histologically confirmed liver cirrhosis. The levels of caffeine, paraxanthine, theobromine, and theophylline were monitored over 10 h in plasma and bile before and after a prior oral dose of caffeine (5 mg/kg b. wt.). Methylxanthines were enriched by an organic extraction procedure and separated by reversed-phase high-performance liquid chromatography. Time-concentration curves in bile paralleled the time-course of methylxanthine levels in blood plasma. Accordingly, values in bile and blood plasma were highly correlated for each methylxanthine measured. Within 1 h after the oral test dose, peak levels of caffeine were obtained in both fluids. Biliary concentrations were either almost equal (caffeine) or lower (dimethylxanthines) than their respective values in blood plasma. The results of our study indicate that minor amounts of caffeine and its primary degradation products are excreted via the bile allowing local interference with epithelial cell metabolism of bile ducts and gallbladder.
Adult↗
High concentrations of soluble tumor necrosis factor receptors in ascites.
Ascites and plasma concentrations of soluble tumor necrosis factor receptors p55 and p75 were measured in a prospective study in 34 patients (35 occasions of ascites) with hepatic (5 infected and 21 uninfected) and malignancy-related (9) ascites. All patients had high concentrations of both soluble tumor necrosis factor receptors in ascites and plasma; these were about 500 times higher than the corresponding tumor necrosis factor-alpha concentrations. Ascites levels of soluble tumor necrosis factor receptors p55 and soluble tumor necrosis factor receptors p75 were significantly elevated in patients with malignancy-related (p55: 26.0 +/- 8.6 ng/ml; p75: 20.5 +/- 17.4 ng/ml; mean +/- S.D.) and infected ascites (p55: 25.1 +/- 10.9 ng/ml, p75: 22.6 +/- 11.0 ng/ml) compared with patients with uncomplicated hepatic ascites (p55: 10.1 +/- 4.4 ng/ml; p75: 6.0 +/- 2.6 ng/ml). Patients with infected or malignancy-related ascites also showed higher soluble tumor necrosis factor receptor concentrations in plasma than did patients with plain hepatic ascites. Successful antibiotic treatment of peritonitis reduced soluble tumor necrosis factor receptor p55 and p75 ascites levels in three patients from 24.2 +/- 15.2 ng/ml to 10.7 +/- 1.9 ng/ml and from 20.2 +/- 14.4 ng/ml to 7.5 +/- 1.8 ng/ml, respectively. Soluble tumor necrosis factor receptors p55 and p75 at cutoff levels of 16.5 ng/ml and 9.5 ng/ml, respectively, differentiated between infected or malignant and plain hepatic ascites with diagnostic accuracies of 94% and 89%, respectively. They did not differentiate between infected and malignant ascites. The concentrations of soluble tumor necrosis factor receptor p55 were usually higher in ascites than in plasma in all subgroups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Evidence for the production of high amounts of interleukin-6 in the peritoneal cavity of patients with ascites.
The ascites and serum concentrations of interleukin-6 (IL-6) and interleukin-1 (IL-1) were determined in 21 patients with hepatic ascites and in 9 patients with malignancy-associated ascites. There was no evidence for bacterial peritonitis in any patients. All ascites samples contained high amounts of immunoreactive IL-6 [hepatic ascites 1730 +/- 2130 pg/ml (mean +/- SD), 1160 pg/ml (median); malignant ascites 4020 +/- 1510 pg/ml (mean), 3820 pg/ml (median)] but no IL-1. The mean ascites to serum ratios of IL-6 were 96 (median 49) in patients with hepatic ascites and 587 (median 480) in patients with malignant ascites. Ascites IL-6 was biologically active as determined by the B9 cell bioassay. The results indicate that even in the absence of infection IL-6 is produced in high amounts in the peritoneal cavity of patients with hepatic or malignant ascites.
Adult↗
Uridine catabolism by the isolated perfused rat liver.
A new approach in the treatment of gastrointestinal tumors with 5-fluorouracil involves the infusion of high doses of uridine to improve the chemotherapeutic efficiency of the former. High amounts of uracil formed from uridine can interfere with the hepatic catabolism of 5-fluorouracil and thus increase its bioavailability and toxicity. In our study, we analysed the metabolite pattern of uridine in the effluent of isolated perfused rat livers in relation to portal uridine levels. The livers were perfused hemoglobin-free without recirculation at a constant flow. In the perfusate, uridine was changed from 0.5 to 100 mumol/l. The complete degradation of [2-14C]uridine and [2-14C]uracil was monitored via the release of labeled CO2. Radioactive catabolites of uridine including uracil and the sum of dihydrouracil and beta-ureidopropionate were separated by high-performance liquid chromatography and counted using a radioactivity flow monitor. Portal uridine concentrations were increased from 0.5 to 100 mumol/l and were accompanied by a rise in the relative amount of non-metabolized uridine in the effluent from 13 to 78%. At uridine concentrations above 50 mumol/l, there was a constant release of uracil into the effluent, indicating saturation of uridine phosphorolysis or transport. The amount of 14CO2 formed by the liver reflecting complete uridine breakdown was higher than any other uridine metabolite when uridine concentration varied from 0.5 to 15 mumol/l. Saturation of 14CO2 formation was achieved at a uridine concentration of 25 mumol/l. Higher peak values of 14CO2 release were observed after direct infusion of equivalent amounts of uracil into the portal vein.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Facilitated diffusion and sodium-dependent transport of purine and pyrimidine nucleosides in rat liver.
In mammalian cells, nucleoside transport usually is mediated by facilitated diffusion. In addition, a Na(+)-dependent, concentrative nucleoside transport system has been detected in several tissues but not the liver. To further clarify hepatic nucleoside transport mechanisms, we measured the uptake of [2-14C]uridine (2 to 100 mumol/L) and of [8-14C]adenosine (10 to 75 mumol/L) by the isolated perfused rat liver in the presence or absence of extracellular sodium or specific inhibitors of facilitated nucleoside diffusion. Uridine transport and metabolism were monitored by the release of labeled catabolites including 14CO2, which indicated complete degradation of the pyrimidine. Adenosine, uridine and uridine catabolites were measured in the effluent perfusate by reversed-phase high-performance liquid chromatography and a radioactivity flow monitor. The existence of a Na(+)-dependent nucleoside transport system could be inferred from the following observations: (a) Sodium depletion caused a strong inhibition of nucleoside transport reflected by an up to threefold and 15-fold increase in extracellular uridine and adenosine, respectively. The sodium-dependent transport of uridine was saturated when the influent uridine concentration was raised beyond 20 mumol/L. No such saturation was observed for much higher concentrations of adenosine used (10 to 75 mumol/L). (b) Na(+)-free perfusion resulted in a strong suppression of the release of uridine catabolites by the liver. Complete uridine breakdown was depressed to 7% of the amount of 14CO2 released in the presence of sodium and at influent uridine concentrations below 20 mumol/L. (c) Inhibition of uridine (10 mumol/L) transport and degradation was observed after coperfusion with adenosine, deoxyadenosine, guanosine and deoxyguanosine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Aetiology and pathophysiology of chronic liver disorders.
The aetiology of chronic liver disease covers a wide range of congenital or acquired abnormalities of the hepatocellular biochemical network. Although our knowledge has considerably increased in recent years, the aetiology of chronic liver disease often remains obscure. Acquired irreversible disturbances of normal liver function can be mediated by hepatotrophic viruses, chemicals, chronic oxygen depletion, or interference with the immune system. Considerable progress has been made in the detection and characterisation of hepatitis B, C, and D viruses as causative agents of chronic active hepatitis. Alcohol abuse remains the predominant cause of chronic liver disease in the Western world. The targets of autoantibodies used to diagnose autoimmune diseases of the liver and primary biliary cirrhosis continue to be biochemically defined. Their significance for the aetiology of the disease, however, remains to be established. Nonparenchymal cells play an important role in the sequence of events following hepatocellular injury and ultimately leading to liver cirrhosis. They release vasoactive compounds, cytokines, and other important mediators, and participate in the modulation of the extracellular matrix that is characteristic of liver fibrosis and cirrhosis. The biochemical basis of liver cell necrosis remains poorly defined. In spite of recent progress, and the detection of some new pathogenic principles that help in the understanding of the complications of chronic liver disease such as portal hypertension, oesophagogastric variceal bleeding, portosystemic encephalopathy, ascites, and other metabolic disturbances, many questions concerning the aetiology and pathophysiology of chronic liver disease and its complications remain to be answered.
Ascites↗
[Therapy and prevention of hemorrhage from esophageal varices].
Management of variceal hemorrhage includes emergency treatment of bleeding esophageal varices and prophylactic treatment for the prevention of first bleeding or rebleeding. Endoscopic injection sclerotherapy appears to be the most effective therapeutic option to control acute variceal hemorrhage. When sclerotherapy fails or cannot be performed a Sengstaken-Blakemore tube can be used. Supportive treatment is provided by vasodilator or vasoconstrictor therapy. At present, operative treatment modalities such as portosystemic shunts or esophageal transection are secondary to sclerotherapy or balloon tamponade. The probability of recurrent variceal hemorrhage after a first bleeding is 70%. This necessitates preventive measures such as endoscopic sclerotherapy, beta-blockade, or surgical procedures. Meta-analysis of randomised controlled trials indicates that sclerotherapy appears to reduce the number of episodes of recurrent variceal hemorrhage better than other prophylactic treatments and to improve survival. Chronic sclerotherapy may be the procedure of first choice in patients with good liver function when elective shunt surgery is provided for those who have recurrent bleeding despite sclerotherapy. The role of beta-blockade in the prevention of recurrent bleeding remains to be clearly defined. Prevention of first esophageal bleeding by invasive treatment modalities could reasonably only be performed in patients with high bleeding risk, which, however, cannot be defined accurately at present. The use of beta-blockers in the prevention of first variceal hemorrhage should be restricted to clinical trials.
Combined Modality Therapy↗
[Epidemiology and pathogenesis of gallstones. Status of knowledge and therapeutic consequences].
The prevalence of gallstones in Europe is 7% for mean and 12 to 14% for women with figures increasing with age. Most gallbladder stones remain asymtomatic, leading to complications in less than 2%, and to biliary pain in 18% of initially asymptomatic patients over a period of 20 years. On the basis of such observations it has been concluded that only symptomatic gallbladder stones need to be treated. Stones in the bile ducts, however, must be removed whether symptomatic or not. In Europe more than 80% of gallbladder stones are cholesterol stones. The remaining stones are black pigment stones, composed predominantly of calcium bilirubinate. Brown pigment stones usually occur in the pathogenesis of cholesterol stones, may lead to new therapeutic or prophylactic approaches.
Cholelithiasis↗
Correlation of caffeine elimination and Child's classification in liver cirrhosis.
Apparent pharmacokinetic parameters of caffeine elimination from the circulation were determined in 27 patients with histologically confirmed liver cirrhosis, 8 patients with miscellaneous liver disease, and 8 patients with other than liver disease. The usefullness of this quantitative test to assess the severity of liver cirrhosis was compared to the Child-Turcotte or Child-Pugh classification score as well as to the galactose elimination capacity of these patients. Using reversed-phase high pressure liquid chromatography caffeine, paraxanthine, theophylline, and theobromine were analysed in blood plasma collected before and after an oral dose of caffeine. Compared to apparent caffeine pharmacokinetics in patients with normal livers or miscellaneous liver disease, cirrhosis was characterized by a statistically significant reduction in apparent caffeine clearance and prolongation in half-life. The reduced apparent plasma disappearance rate of caffeine in cirrhotics was related to the retarded formation of paraxanthine which was the main metabolite of caffeine in blood plasma both in the absence or presence of liver disease. The apparent caffeine clearance in cirrhosis decreased with increasing Child-Turcotte classification score: Child's class A patients differed significantly from Child's class B or Child's class C patients, whereas the difference between Child's class B and C patients did not reach statistical significance (Wilcoxon's rank test). In addition there was a strong correlation between the Child-Pugh classification score and apparent caffeine clearance (P less than 0.001). However, no correlation existed between Child's classification and galactose elimination capacity. Our data emphasize the value of the Child-Turcotte or Child-Pugh classification in assessing the severity of liver cirrhosis in a simpler and less time-consuming way than using quantitative liver function tests.
Administration, Oral↗
The role of nonparenchymal and parenchymal liver cells in the catabolism of extracellular purines.
Adenosine-degrading enzymes within the liver lobule can modulate both vascular and metabolic effects of circulating adenosine in the liver. Since it has not been fully established whether nonparenchymal cells participate in the elimination of sinusoidal purines, isolated Kupffer cells and endothelial cells were tested for their capacity to degrade extracellular purines. After perfusion and digestion of rat livers by collagenase, the resulting mixed cell population was separated by centrifugal elutriation. The isolated parenchymal and nonparenchymal cells were incubated for up to 2 hr in the presence of [8(-14)C]adenosine, [8(-14)C]guanosine and [8(-14)C]hypoxanthine (50 mumoles per liter). In the deproteinized medium, adenosine, guanosine, inosine, adenine, guanine, xanthine, hypoxanthine, uric acid and allantoin were separated by reversed-phase high-performance liquid chromatography. Radioactive peaks were collected and counted. Nonparenchymal cells catalyzed the degradation of adenosine into inosine and hypoxanthine. However, the formation of xanthine, uric acid or allantoin from adenosine could only be detected in hepatocyte suspensions. Within 15 min, adenosine was completely eliminated from the medium by Kupffer cells, whereas endothelial cells catabolized only less than half of the initial amount of the adenine nucleoside during this time period. Accordingly, incubation of nonparenchymal cells in the presence of hypoxanthine did not result in the formation of further breakdown products of the purine, whereas its catabolites slowly accumulated in the medium of hepatocytes. Guanosine conversion into guanine and xanthine was much slower in endothelial cells as compared to Kupffer cells and hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗