[Surgical and conservative treatment of liver diseases].
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Biliary Tract Diseases↗
Biomedical subjects
J Reichen
Publications and source records attributed to J Reichen.
[Liver injury under tuberculostatic treatment].
We report the case of a patient with nausea, loss of appetite and increase of the aminotransferase levels to eight times the upper normal limit occurring two weeks after she was started on isoniazide, rifampicine and pyrazinamide for treatment of tuberculosis. Isoniazide is the most likely cause of liver injury occurring during combined antituberculosis therapy, whereas pyrazinamide or rifampicine are only rarely responsible. The case presented is used to review and compare the different recommendations concerning the monitoring of patients receiving antituberculous therapy and the clinical management of patients developing liver injury.
Aged↗
[Are diuretics in the treatment of portal hypertension rational?].
When ascites develops in a patient with cirrhosis his probability to survive the following 2 years amounts to 50%. It is determined essentially by the residual functional capacity of the liver. In 80 to 90% of patients ascites due to portal hypertension can be managed by salt restriction and diuretics. Aldosterone-antagonists are more efficient and have fewer side effects than loop diuretics. They may lower portal tension by an additional direct effect on the vasculature. A daily reduction of body weight of 0.5 to 0.75 kg should not be exceeded because (prerenal) renal failure may become a threat. If diuretics are insufficient or when a rapid therapeutic success is needed paracentesis of 4-6.1 is a safe option if intravascular volume is substituted simultaneously. Albumin has proven superior to other plasma expanders (protection of renal function, survival). Only in the few patients whose ascites is intractable by the forementioned measures should alternatives such as peritoneo-, venous or porto-systemic shunts (nowadays mostly by interventional techniques via a transjugular catheter) be evaluated. The only treatment which not only attacks ascites symptomatically but also corrects the underlying disease is liver transplantation.
Ascites↗
Ectopic expression of the calcium-binding protein parvalbumin in mouse liver endothelial cells.
To elucidate the physiological role of the Ca2+ binding protein parvalbumin, we have generated transgenic mice carrying the full-length complementary DNA (cDNA) of rat parvalbumin under the control of the heavy-metal inducible metallothionein IIA promoter. Immunohistochemical and biochemical methods have been used to detect the presence of ectopic parvalbumin expression in different tissues. Here we show the expression of parvalbumin in endothelial cells lining the liver sinusoids in situ and after isolation in vitro. The hemodynamic effects of endothelin 1, a peptide hormone mediating potent vasoconstriction via calcium signalling, were investigated in the mouse liver perfused in situ. Vasoconstriction, thought to be mediated by the Ito cell, was not affected in the transgenic animals, whereas microvascular exchange, probed with the multiple indicator dilution technique, was markedly decreased in normal mice but virtually not affected in the transgenic animals. This suggests that ectopically expressed parvalbumin is involved in the regulation of Ca2+ signals in the sinusoidal endothelial cells. This animal model could be of interest to those working on the physiology of liver circulation.
Animals↗
Hepatic mitochondrial proliferation in rats with secondary biliary cirrhosis: time course and mechanisms.
It is well known that the hepatic mitochondrial protein content is increased in rats 4 weeks after bile duct ligation. In the present study, we measured the time course of this increase and assessed the levels of selected mitochondrial messenger RNA (mRNA) species and the rate of mitochondrial protein synthesis by isolated mitochondria. Three days after surgery, the mitochondrial protein content was not significantly different between bile duct-ligated (BDL) and control rats, averaging 1,140 +/- 220 mg/liver in BDL and 1,260 +/- 50 mg/liver in sham-operated control rats. However, in comparison with control rats, it was increased in BDL rats by 35% at 7 days, by 81% at 14 days, and by 27% at 28 days after surgery. In vitro mitochondrial protein synthesis, which was assessed as the fractional incorporation of [35S]-methionine into mitochondrial protein, was not different between BDL and control rats at 3 days after surgery, but was decreased in BDL rats by 63% at 7 days, by 55% at 14 days, and by 36% at 28 days after surgery. Northern blot analysis revealed an increase in the mRNA levels of adenosine triphosphate (ATP)ase subunit 6 and apocytochrome b in BDL rats at day 7, but no significant differences between BDL and control rats in mitochondrial mRNA and ribosomal RNA species 14 and 28 days after surgery. These results show that the hepatic mitochondrial protein content rises early after surgery in BDL rats, but this rise cannot be ascribed to elevated rates of mitochondrial protein synthesis. Thus, increased synthesis of nuclearly encoded mitochondrial proteins and/or decreased degradation of mitochondrial proteins appear likely mechanisms that lead to the observed increase in the hepatic mitochondrial protein content in BDL rats.
Animals↗
Targeting naproxen coupled to human serum albumin to nonparenchymal cells reduces endotoxin-induced mortality in rats with biliary cirrhosis.
Endotoxin is thought to play a major role in cirrhotic liver disease. Cyclo-oxygenase inhibitors were shown to be partially protective against endotoxin but cannot be used in cirrhotic patients because of renal side-effects. We argued that administration of naproxen (NAP) linked to human serum albumin (HSA), which results in specific delivery of NAP to endothelial cells (EC) and Kupffer cells (KC) and exhibited hepatoprotective effects against lipopolysaccharide (LPS) in vitro, could protect cirrhotic rats from LPS toxicity while preserving renal function. The studies were performed in rats rendered cirrhotic by bile duct ligation (BDL); animals received LPS (Escherichia coli, 800 microg/kg) intravenously. Five groups were studied: LPS alone, rats pretreated with a conventional dose of NAP (50 mg/kg), NAP-HSA (22 mg/kg), NAP equimolar to NAP-HSA (1.5 mg/kg), or the HSA carrier. LPS induced significant mortality (55%); this was not affected by equimolar NAP (57%) but accentuated by conventional NAP (88%). In contrast, NAP-HSA provided significant protection (9%; P < .05). After conventional NAP treatment, significant renal toxicity was observed as evidenced by a marked reduction in sodium excretion (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 33 +/- 22 vs. 50 +/- 39 vs. 4 +/- 3 micromol/h; P < .05). Renal prostaglandin E2 (PGE2) excretion was reduced by NAP in all groups, but most markedly at the conventional dosage (LPS vs. NAP-HSA vs. NAP [50 mg/kg] 132 +/- 115 vs. 39 +/- 19 vs. 9 +/- 8 ng/mL; P < .05). Successful targeting was evidenced by a significant hepatic enrichment of NAP in the NAP-HSA group compared with the equimolar untargeted group (30.16 +/- 9.33 vs. 1.13 +/- 1.95 nmol/g liver). Thus, targeting NAP to EC/KC results in improved survival, higher efficacy, and sparing of renal function in cirrhotic rats.
Animals↗
[Liver transplantation in a small center: feasibility, efficacy and prospects].
Today, orthotopic liver transplantation is the treatment of choice for the end-stage of various liver diseases, and a 1-year survival rate of 80% and a 5-year survival rate of 70% in elective patients without tumor are reported in international surveys. The liver transplant programme of the Inselspital in Bern is small compared with international centres, which may raise questions about the results and the justification for such a programme. Over a period of 66 months, 62 liver transplantations were performed in 60 patients at the Inselspital. The hospital mortality was 3.3%, and the 2.5-year overall survival rate was 92% for elective cases without tumor. After a median follow-up of 30 months, 68% of all patients were re-integrated in housework or full- or part-time in their profession, and 83% were independent from the help of others. We conclude that a small liver transplant programme based only on routine resources can achieve results comparable to the international standards.
Academic Medical Centers↗
Detection and characterization of mitochondrial DNA rearrangements in Pearson and Kearns-Sayre syndromes by long PCR.
We used a strategy based on long PCR (polymerase chain reaction) for detection and characterization of mitochondrial DNA (mtDNA) rearrangements in two patients with clinical signs suggesting Pearson syndrome and Kearns-Sayre syndrome (KSS), respectively, and one patient with myopathic symptoms of unidentified origin. Mitochondrial DNA rearrangements were detected by amplification of the complete mitochondrial genome (16.6 kb) using long PCR with primers located in essential regions of the mitochondrial genome and quantified by three-primer PCR. Long PCR with deletion-specific primers was used for identification and quantitative estimation of the different forms of rearranged molecules, such as deletions and duplications. We detected significant amounts of a common 7.4-kb deletion flanked by a 12-bp direct repeat in all tissues tested from the patient with Pearson syndrome. In skeletal muscle from the patient with clinical signs of KSS we found significant amounts of a novel 3.7-kb rearrangement flanked by a 4-bp inverted repeat that was present in the form of deletions as well as duplications. In the patient suffering from myopathic symptoms of unidentified origin we did not detect rearranged mtDNA in blood but found low levels of two rearranged mtDNA populations in skeletal muscle, a previously described 7-kb deletion flanked by a 7-bp direct repeat and a novel 6.6-kb deletion with no repeat. These two populations, however, were unlikely to be the cause of the myopathic symptoms as they were present at low levels (10-40 ppm). Using a strategy based on screening with long PCR we were able to detect and characterize high as well as low levels of mtDNA rearrangements in three patients.
Adolescent↗
Effect of ethanol and fructose on liver metabolism: a dynamic 31Phosphorus magnetic resonance spectroscopy study in normal volunteers.
In vivo 31Phosphorus magnetic resonance spectroscopy (31P-MRS) permits evaluation of dynamic changes of individual phosphorus-containing metabolites in the liver parenchyma, such as phosphomonoester (PME), adenosine triphosphate, and inorganic phosphate (Pi). Intravenous fructose load alters phosphorus metabolites and allows assessment of liver function by 31P-MRS. 31P-MRS data obtained in alcoholic liver disease are however inconclusive. To study the hypothesis that fructose load can be used to investigate metabolic effects of ethanol ingestion, the interaction of different metabolites--i.e., fructose and ethanol--were followed in vivo. Using a 1.5 Tesla magnetic resonance system, six healthy volunteers were examined in three sessions each: a session after administration of (a) fructose only (250 mg/kg) was compared with (b) fructose load after ethanol ingestion (0.8 g/kg). A control experiment (c) was done after ethanol only. Spectra were acquired using one-dimensional chemical shift imaging with a temporal resolution of 5 min. Following a fructose load, the concomitant uptake of ethanol showed drastic changes of individual metabolic steps of the hepatic metabolism (averages +/- standard deviation). While the velocity of the net formation of PME (relative increase 0.46 +/- 0.11 without ethanol vs. 0.61 +/- 0.25 with ethanol) and the use of adenosine triphosphate (-0.13 +/- 0.03 vs. -0.16 +/- 0.03) and Pi (-0.022 +/- 0.009 vs. -0.021 +/- 0.004) were not significantly affected by ethanol uptake, a significant (p < 0.01) reduction of PME degradation (31.3 +/- 9.4 vs. 61.9 +/- 16.9 relative total area) and absence of an overshoot for Pi (10.5 +/- 4.9 vs. -7.1 +/- 5.3 relative area 13 min to 43 min) was observed after ethanol administration. Dynamic 31P-MRS allows the observation of individual steps of hepatic metabolism in situ; fructose metabolism in the human liver is slowed down by concomitant ethanol ingestion after the phosphorylation step of fructose. This could be explained by inhibition of aldolase rather than ethanol-induced changes of the hepatic redox state. Fructose load can be used to study effects of alcohol ingestion and might therefore be useful in patients with alcoholic liver disease.
Adenosine Triphosphate↗
Dynamic phosphorus-31 spectroscopy after fructose load in experimental biliary liver cirrhosis.
RATIONALE AND OBJECTIVES: The authors investigated the usefulness of dynamic phosphorus-31 magnetic resonance (MR) spectroscopy in the assessment of hepatic function by studying the effect of a fructose load on a rat model of liver cirrhosis. METHODS: In vivo P-31 MR liver spectra of eight rats with bile duct ligature and 10 control rats were obtained every 4.6 minutes before and after intraperitoneal fructose load (10 mmol per kilogram of body weight). RESULTS: In the basal spectra of the experimental group, the phosphomonoester peak was higher than in the control group (P = .026). After the fructose load, the phosphomonoester peak increase and the inorganic phosphate peak decrease were significantly less marked in the experimental group (P = .003). There was a linear correlation between the serum level of bilirubin and the phosphomonoester increase (r = .61, P < .001). CONCLUSION: Dynamic P-31 MR spectroscopy may be useful in the assessment of hepatic function in chronic liver disease.
Analysis of Variance↗
Carnitine metabolism in patients with chronic liver disease.
Carnitine metabolism was studied in 79 patients with chronic liver disease, including 22 patients with noncirrhotic liver disease and 57 patients with different types of cirrhosis (22 patients with hepatitis B- or C-associated cirrhosis, 15 patients with alcohol-induced cirrhosis, 15 patients with primary biliary cirrhosis [PBC], and 5 patients with cryptogenic cirrhosis), and compared with 28 control subjects. In comparison with control subjects, patients with noncirrhotic liver disease showed no change in the plasma carnitine pool, whereas patients with cirrhosis had a 29% increase in the long-chain acylcarnitine concentration. Analysis of subgroups of patients with cirrhosis showed that patients with alcohol-induced cirrhosis had an increase in the total plasma carnitine concentration (67.8 +/- 29.5 vs. 55.2 +/- 9.9 micromol/L in control subjects), resulting from increases in both the short-chain and long-chain acylcarnitine concentration. In this group of patients, the acylcarnitine concentrations showed a close correlation with the total carnitine concentration, and the total carnitine concentration with the serum bilirubin concentration. Urinary excretion of carnitine was not different between patients with noncirrhotic or cirrhotic liver disease and control patients. However, patients with PBC showed an increased urinary excretion of total carnitine (52.5 +/- 40.0 vs. 28.0 +/- 16.7 micromol carnitine/mmol creatinine), resulting from an increase in the fractional excretion of both free carnitine and short-chain acylcarnitine. The current studies show that patients with cirrhosis are normally not carnitine deficient. Patients with alcohol-induced cirrhosis have increased plasma carnitine concentrations, which may result from increased carnitine biosynthesis because of increased skeletal muscle protein turnover. The increase in the fractional carnitine excretion in patients with primary biliary cirrhosis may result from competition of bile acids and/or bilirubin with tubular carnitine reabsorption and/or from a reduced activity of the carnitine transporter located in the proximal tubule.
Adult↗
Benzoic acid metabolism reflects hepatic mitochondrial function in rats with long-term extrahepatic cholestasis.
Benzoic acid metabolism, which is primarily a function of liver mitochondria, depending on the concentration of adenosine triphosphate (ATP), coenzyme A (CoA), and glycine in the mitochondrial matrix, was investigated in both rats with long-term cholestasis caused by bile duct ligation (BDL) and sham-operated control rats. In isolated liver mitochondria, hippurate production from benzoate in the presence of saturating glycine concentrations was reduced in BDL rats by 36% with L-glutamate as a source for ATP, by 21% in the presence of succinate, and by 31% in the presence of ATP plus oligomycine. This reduction in benzoate metabolism is in the same range as the previously observed reduction in the activity of the electron transport chain in liver mitochondria from BDL rats. The mitochondrial CoA pool, which can be rate-limiting for benzoic acid metabolism, was not different between BDL and control rats. The activity of benzoyl-CoA synthase, the enzyme catalyzing the rate-limiting step in benzoate metabolism, was reduced by 25%, and the activity of benzoyl-CoA:glycine N-transferase was reduced by 66% in BDL rats. The activity of benzoyl-CoA synthase was significantly inhibited by lithocholate, suggesting that hepatic accumulation of hydrophobic bile acids could contribute to the observed reduction of benzoate metabolism in BDL rats. Benzoate metabolism was also studied in vivo by monitoring the urinary hippurate excretion after intraperitoneal administration of benzoate (100 micromol/100 g of body weight). The time course of hippurate excretion was not different between BDL and control rats. Hippurate excretion over 24 hours after benzoate administration averaged 89.7 +/- 4.0% of the administered dose in BDL and 74.4 +/- 6.9% (mean +/- SEM, difference not significant) in control rats. This finding could be explained by an increase in mitochondrial protein in BDL rats, averaging 2.34 +/- 0.29 g per liver in BDL and 1.35 +/- 0.07 g per liver in control rats (mean +/- SEM, p < .05). Thus, the studies show that benzoate metabolism reflects mitochondrial function in BDL rats both in vivo and in vitro, and that mitochondrial proliferation compensates for the observed decrease in benzoic acid metabolism in isolated mitochondria in vitro.
Animals↗
Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study.
The objectives were to determine quantitative liver function prospectively in patients with rheumatoid arthritis (RA) treated with low-dose methotrexate (MTX), to search for risk factors for a loss of quantitative liver function and to assess the relationship between quantitative liver function and histological staging. A total of 117 patients with RA (ACR criteria, 85 women, mean age 59 yr) had measurements of galactose elimination capacity (GEC), aminopyrine breath test (ABT) and liver enzymes [aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (AP), 7-glutamyl transferase (GGT), bile acids, bilirubin, albumin] before treatment with weekly i.m. MTX injections and every year thereafter. In 16 patients, liver biopsies were performed. Before the introduction of MTX, mean GEC was 6.6 mg/min/kg [5th to 95th percentile (5-95 PC) 5.1-8.5; reference range 6.0-9.1] and mean ABT was 0.80% kg/mmol (5-95 PC 0.42-1.30: reference range 0.6-1.0). During treatment with MTX [mean weekly dose 11.8 mg (5-95 PC 5.4-20.2), mean observation period 3.8 yr (5-95 PC 0.4-6.9)], significant declines of GEC (-0.12 mg/min/kg per year. t = 3.30, P < 0.002) and ABT (-0.06% kg/mmol per year, t = 4.81, P < 0.001) were observed. Negative correlations were found between the annual change in GEC and GEC at baseline (Rs = -0.40, P < 0.0001), and the annual change in ABT and ABT at baseline (Rs = -0.43, P < 0.0001). No correlations were found between the annual change in GEC or ABT and weekly MTX dose, age or percentage of increased liver enzymes, and no effect of a history of alcohol consumption > 30 g/week became evident. Two patients with Roenigk grade III had impaired quantitative liver function, while 14 patients with Roenigk grades I and II exhibited a high variability of GEC and ABT from normal to abnormal values. The continuous declines in GEC and ABT observed deserve attention in patients with prolonged treatment. Patients with a low GEC or ABT at baseline seem not to be at increased risk for a further loss of quantitative liver function. An impaired GEC or ABT does not necessarily concur with hepatic fibrosis on histological examination.
Alanine Transaminase↗
Targeting naproxen to non-parenchymal liver cells protects against endotoxin induced liver damage.
Non-steroidal anti-inflammatory drugs (NSAID's) could be of value in the treatment of liver disease; however, their use in this situation is limited by renal side effects. Therefore, we explored whether naproxen covalently bound to human serum albumin NAP-HSA) was able to reduce toxicity in an acute model of liver disease induced by endotoxin in rats pretreated with Corynebacterium parvum. In the isolated perfused liver of such animals endotoxin induced cholestasis (0.62 +/- 0.05 vs. 0.24 +/- 0.09 microliter.min-1.g liver-1; p < 0.05), increased vascular resistance (11300 +/- 400 vs. 311000 +/- 2000 dyn.s.cm-5; p < 0.05) and alanine aminotransferase release (22 +/- 9 vs. 149 +/- IU/l; p < 0.05). At the highest dose tested (22 mg/kg, corresponding to 6.0 mumoles naproxen), NAP-HSA normalized ALT release (21 +/- 10 IU/l: p < 0.05) while an equimolar amount of non-targeted naproxen was only partially effective (56 +/- 19 IU/l). A conventional dose of naproxen similarly prevented transaminase release. Cholestasis and increased vascular resistance were also prevented by NAP-HSA. Drug targeting by linking drugs to proteins is a potentially useful approach to maximizing drug effect while minimizing adverse events; this could be particularly useful for compounds with potentially serious adverse effects in patients with chronic liver disease such as the nonsteroidal anti-inflammatory agents used in the present study.
Animals↗
[Liver transplantation at the Bern Island Hospital: results from the last 5 years].
Today, orthotopic liver transplantation (OLT) is the treatment of choice for the endstage of various liver diseases, a 1-year survival rate of 80% and a 5-year survival rate of 70% in elective patients without tumor is reported in international surveys. The liver transplant program of the Inselspital Bern is very small compared with international centers, and this may raise questions about the (long-term) results and the justification for such a program. During the last 63 months, 59 liver transplantations (including two retransplants) have been performed in 57 patients at the Inselspital. The 30-day mortality was 3.5% and the 2.5-year overall survival rate was 82% and 93% for elective cases without tumor. After a median follow-up of 29 months, 67% of all patients were reintegrated fully or part-time in their profession and 81% were independent of others' help. We conclude that even a small liver transplant program based on routine resources only can achieve results which are comparable to international standards.
Adult↗
Differentiation between naproxen, naproxen-protein conjugates, and naproxen-lysine in plasma via micellar electrokinetic capillary chromatography--a new approach in the bioanalysis of drug targeting preparations.
Pharmacotherapy through the targeting of drugs is a promising new approach that requires adequate analytical methods capable of differentiating between the free drug, the drug carrier, and metabolites. Using micellar electrokinetic capillary chromatography (MECC), we report the separation of naproxen (NAP) from NAP covalently coupled to human serum albumin or to mannosylated serum albumin and the metabolite naproxen-lysine. An assay for selective analysis of the different forms of NAP by direct plasma injection was developed with salicylate as internal standard and solute detection by laser-induced fluorescence. Compared with previously applied techniques, including HPLC and total plasma fluorescence, MECC offers the advantage that free and covalently bound NAP can be differentiated in one run and can be accurately monitored in microliter quantities of plasma. Summation of all NAP equivalents determined by MECC revealed data that compare well with those produced by total plasma fluorescence and HPLC.
Animals↗
Application of mRNA differential display to liver cirrhosis: reduced fetuin expression in biliary cirrhosis in the rat.
We here show the application of mRNA differential display to investigate changes in gene expression in rat liver cirrhosis and address problems inherent in the technique when applied to this complex disease model. A number of differentially expressed mRNA species could be identified and two were analyzed in more detail here. One was found to derive from a new gene while the other corresponded to fetuin, a 41 kDa N-glycoprotein that specifically inhibits tyrosine kinase activity of the insulin receptor when phosphorylated. Fetuin expression was reduced by 45% in liver cirrhosis induced by bile duct ligation, but not in cirrhosis induced by carbon tetrachloride/Phenobarbital, as compared to controls. Our results raise the possibility that fetuin plays a regulatory role in the proliferation of parenchymal liver cells.
Animals↗