[Ribavirin/interferon-alpha combination in treatment of chronic hepatitis C: what is the status today?].
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Antiviral Agents↗
Biomedical subjects
E L Renner
Publications and source records attributed to E L Renner.
[Therapy of chronic hepatitis C: facing a breakthrough?].
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Amantadine↗
[Drug therapy of chronic hepatitis B].
Medical therapy of chronic hepatitis B aims at halting progression towards cirrhosis/hepatocellular carcinoma by inhibiting replication of hepatitis B virus in a sustained fashion (viral elimination). The sole therapy of proven efficacy is interferon-alpha (5-10 Mio IU sc TIW) which leads within 4 months to viral elimination (seroconversion from HBeAg to anti-HBe-antibody; serum HBV-DNA negative by hybridisation) in approximatively 40% of patients. Interferon-alpha therapy has been shown to decrease hepatitis B associated morbidity/mortality and to be cost-effective. Certain nucleoside analoga such as lamivudine or famciclovir are able to stop hepatitis B virus replication in a large proportion of patients; replication promptly resumes however after cessation of treatment and resistance develops in approximatively 15% of patients treated for one year. The clinical value, in particular for interferon-alpha non-responders, of a combination of interferon-alpha and/or nucleoside analoga remains to be seen.
2-Aminopurine↗
Quality of life after liver transplantation.
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Adult↗
Hepatocellular defence against acidosis is preserved after cold storage.
BACKGROUND: Primary non-function of liver allografts is related to preservation time, during which hypoxia leads to intracellular accumulation of acid. Preservation-induced failure of hepatocellular pH regulation may play a role in the pathogenesis of primary graft non-function. METHODS: Using cultured/suspended rat hepatocytes and fluorimetric determination of intracellular pH, we determined whether preservation in University of Wisconsin solution (4 degrees C) impairs hepatocellular defence mechanisms against acidosis. RESULTS: In non-preserved, 24-h-preserved and 48-h-preserved hepatocytes acidified to pH 6.7-6.8, initial Na+/H+ antiport-mediated H+ fluxes averaged 12 +/- 5, 9 +/- 5 and 12 +/- 5 nmol microL-1 min-1 and initial Na+/HCO3- symport-mediated HCO3- fluxes 7 +/- 2, 7 +/- 3 and 6 +/- 2 nmol microL-1 min respectively (P = NS). Preservation did not affect the inverse relationship between Na+/H+ antiport activity and intracellular pH. Thus, hepatocellular defence against intracellular acidosis is maintained during up to 48 h in University of Wisconsin solution. CONCLUSION: Altered pHi homeostasis is unlikely to play a role in the pathogenesis of primary non-function of liver allografts.
Acidosis↗
[Management of the liver transplant patient].
The general practitioner plays a crucial role in the care for the liver transplant recipient. The number of liver transplant recipients increasing steadily by about 50 a year in Switzerland, the practitioner will increasingly be confronted with such patients. A close cooperation between general practitioner and transplant center is mandatory and the key to success. This paper aims at introducing the general practitioner to the care for the liver transplant recipient.
Humans↗
[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↗
[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↗
[Esophageal varices].
Variceal hemorrhage still carries a high mortality and a high risk of recurrence. Esophageal varices bleed rarely with a porto-systemic pressure gradient below 12 mmHg; pharmacotherapy, thus, aims at lowering the pressure gradient below this critical threshold. Conceptually, this can be achieved by decreasing portal-venous inflow (via lowering cardiac output and/or increasing splanchnic-arteriolar vasoconstriction) or by decreasing portal-venous resistence (via portal vasodilation). In acute variceal bleeding, easily applicable pharmacotherapy with terlipressin plus nitroglycerin, probably also with octreotide, can help to stabilize the patient and to buy time until diagnostic endoscopy and treatment by sclerotherapy or variceal band ligation. For pharmacotherapeutic secondary prophylaxes of variceal hemorrhage the combination of propranolol or nadolol with isosorbid-5-mononitrate is available. Future studies will tell, whether this drug combination is superior to the nowadays established endoscopic eradication of varices, especially by long-term variceal band ligation. For primary prophylaxis of variceal hemorrhage non-selective beta-anatagonists remain the therapy of choice in compliant patients with esophageal varices and endoscopic signs indicating a high risk of bleeding. Future studies must clarify the role of the beta-antagonist-nitrate combination, as well as that of prophylactic variceal band ligation, in this setting.
Adrenergic beta-Antagonists↗
Fixed versus titrated interferon-alpha 2B in chronic hepatitis C. A randomized controlled multicenter trial. The Swiss Association for the Study of the Liver.
BACKGROUND/AIM: Interferon has become the mainstay of treatment of chronic hepatitis C; however, duration of treatment and dose remain unresolved questions. The present study aimed to compare standard dose interferon with a titrated dose regimen carried out for 1 year. METHODS: This was a randomized, controlled multicenter trial. Patients with chronic hepatitis C were randomly allocated to a control group (n = 30), to a fixed dose group (n = 31) where interferon-alpha 2b 3 MU thrice weekly was given for 1 year or a titrated group (n = 34) where interferon was titrated starting at 5 MU thrice weekly to the lowest dose keeping the patient in remission as assessed by a normal ALT value. Liver biopsies were obtained before and at the end of treatment; in addition, galactose elimination capacity was measured as a measure of cytosolic function. RESULTS: In the control, fixed and titrated groups a complete response was achieved in 2/29, 10/28 and 15/31, respectively (p < 0.001 in favor of treatment, p = n.s. for the two treatments). The corresponding figure for sustained response was 1/29, 5/28 and 6/ 31 (p = n.s). In the titrated group, a complete (sustained) response was achieved with 5 MU in 2 (2), with 4 MU in 1 (0), with 3 MU in 4 (0), with 2 MU in 3 (0) and with 1 MU in 5 (4). Liver biopsy score and galactose elimination capacity improved significantly in responders but not in treatment failures. CONCLUSIONS: Both fixed and titrated dosing of interferon given for 1 year induced virus clearance in only a minority of treated patients. However, in a small number of patients, a complete and sustained response can be achieved with low doses of interferon. Dose titration could be an interesting approach to decreasing the cost and side effects in the treatment of chronic hepatitis C.
Adult↗
Differential expression of Na+,H(+)-antiporter mRNA in biliary epithelial cells and in hepatocytes.
BACKGROUND/AIMS: Amiloride inhibitable Na+,H(+)-exchange has recently been identified and characterized in rat biliary epithelial cells where its activity at low intracellular pH is significantly higher than in hepatocytes. METHODS: Northern blot and reverse transcription-polymerase chain reaction were used to study the expression of the different Na+,H(+)-antiporter isoforms in isolated biliary epithelial cells and hepatocytes. RESULTS: The present study demonstrates for the first time the expression of Na+,H(+)-antiporter isoform 1 mRNA in rat biliary epithelial cells. Moreover, steady-state levels of this message were several-fold higher in biliary epithelial cells than in hepatocytes. In addition, the expression of Na+,H(+)-antiporter isoform 2 in bile duct epithelial cell but not hepatocytes could be demonstrated by reverse transcription-polymerase chain reaction. CONCLUSIONS: The higher expression of Na+,H(+)-antiporter isoform 1 mRNA may indicate a higher rate of synthesis and therefore a higher Na+,H(+)-exchange activity in biliary epithelial cells than in hepatocytes and is entirely compatible with the results of the previous functional studies.
Animals↗
Decreased constitutive hepatic nitric oxide synthase expression in secondary biliary fibrosis and its changes after Roux-en-Y choledocho-jejunostomy in the rat.
BACKGROUND/AIMS: Inducible nitric oxide synthase (iNOS) in the liver has been shown to increase after stimulation by different compounds. Its exact role in cirrhosis is unclear, but it is thought to be an important factor in the development of the hyperdynamic state. In contrast, little is known about the constitutive form of nitric oxide synthase (cNOS) in the liver, and in particular in liver disease. We therefore investigated immunohistochemical expression of endothelial NOS (cNOS) and, in addition, of macrophage NOS (iNOS), a constitutive and inducible form of NOS, in secondary biliary fibrosis and after reversing these changes by biliodigestive anastomosis. METHODS: Sprague-Dawley rats were allocated to one of seven groups: sham-operated controls (CTR), bile duct ligation for 3 weeks (BDL) and BDL followed by Roux-en-Y choledochojejunostomy (RY); the latter group was studied after 1, 2, 3, 7 and 45 days (RY1, RY2, RY3, RY7, and RY45). cNOS-positive hepatocytes were stained with a monoclonal antibody specifically recognizing this isoenzyme, and quantitated stereologically. RESULTS: Virtually all hepatocytes were positive for cNOS in CTR (99.9 +/- 0.2%); this was markedly reduced in BDL (73.7 +/- 9.8%; p < 0.05). After RY, cNOS positive hepatocytes increased to reach normal levels (99.7 +/- 0.5%) in RY45. In contrast to cNOS, there was no iNOS positive staining with a monoclonal macrophage NOS antibody for this isoenzyme, which was confirmed by determining total iNOS protein concentration by Western blot. Serum nitrite/nitrate concentrations mirrored these findings and decreased from 7.9 +/- 3.7 mol/l in CTR to 2.1 +/- 0.4 mol/l in BDL. After RY, nitrite/nitrate concentration increased to 22.7 +/- 30.1, 32.4 +/- 21.4 and 44.6 +/- 32.7 mol/l in RY1, RY2 and RY3, respectively; in RY45, serum nitrite/nitrate concentration was normal averaging 6.1 +/- 1.2 mol/l. CONCLUSIONS: The present investigation shows that, in secondary biliary fibrosis, endothelial nitric oxide synthase is decreased in hepatocytes, macrophage nitric oxide synthase is not increased, and that-in contrast to current thinking-nitrate/nitrate production is diminished.
Anastomosis, Roux-en-Y↗
[Does serum HCV-RNA-positive hepatitis C differ from serum HCV-RNA-negative hepatitis C?].
Viral RNA is detectable in the serum of the majority but not all patients with chronic hepatitis C. Whether the viremic form differs from the non-viremic form of the disease is unknown. We therefore compared histology (modified Knodell score) and liver function (conventional liver function tests, galactose elimination capacity and aminopyrin breath test) of viremic (n = 45) and non-viremic (n = 37) patients with chronic hepatitis C. Neither the total histologic score, nor any of the individual histologic parameters assessed differed significantly in serum HCV RNA positive and negative patients. Compared to non-viremic subjects, patients with detectable HCV RNA in serum had slightly higher transaminases (p = ns), lower serum albumin (p < 0.05) and decreased galactose elimination capacity (p < 0.05). This trend towards more severe functional hepatic impairment in serum HCV RNA positive patients persisted when cirrhotics and non-cirrhotics were analyzed separately; it fell just short of reaching statistical significance, however, most probably due to the small number of subjects per patient group. The median age of serum HCV RNA positive cirrhotics was 17 years, and that of serum HCV RNA negative cirrhotics 22 years higher than that of the respective non-cirrhotics. Biochemical (transaminases) and histological (intralobular and piece-meal necrosis) markers of disease activity, as well as metabolic functional reserve (aminopyrin breath test, galactose elimination capacity) and histologic severity of fibrosis correlated only loosely (Rs = 0.24-0.56), albeit significantly (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Solvent isotope effect on bile formation in the rat.
2H2O affects many membrane transport processes by solvent and kinetic isotope effects. Since bile formation is a process of osmotic filtration where such effects could be important, we investigated the effects of 2H2O on bile formation in the in situ perfused rat liver. Dose finding experiments showed that at high concentrations, 2H2O increased vascular resistance and induced cholestasis; at 60% 2H2O however, a clear dissociation between the vascular and biliary effects was observed. Therefore, further experiments were carried out at this concentration. The main finding was a reduction in bile salt-independent bile flow from 0.99 +/- 0.04 to 0.66 +/- 0.04 microliters.min-1.g-1 (P < 0.001). This was associated with a 40% reduction in biliary bicarbonate concentration (P < 0.001). Choleretic response to neither taurocholate nor ursodeoxycholate was altered by 2H2O; in particular, there was a similar stimulation of bicarbonate secretion by ursodeoxycholate in the presence of 60% 2H2O. To further elucidate this phenomenon, the effect of 2H2O on three proteins potentially involved in biliary bicarbonate secretion was studied in vitro. 2H2O slightly inhibited cytosolic carboanhydrase and leukocyte Na+/H(+)-exchange, these effects reached statistical significance at 100% 2H2O only, however. In contrast, Cl-/HCO(3-)-exchange in canalicular membrane vesicles was already inhibited by 50% (P < 0.001) at 60% 2H2O. Finally, there was a slight reduction in biliary glutathione secretion while that of the disulphide was not affected. Our results are compatible with an inhibition of canalicular Cl-/HCO(3-)-exchange by 2H2O. Whether this is due to altered hydration of the exchanger and/or of the transported bicarbonate remains to be determined.
Animals↗
Caffeine demethylation measured by breath analysis in experimental liver injury in the rat.
To assess the effects of experimental liver injury on caffeine metabolism, 1 muCi/kg b.w. of [3-methyl 14C]-caffeine (together with 5 mg/kg b.w. of the cold compound) was injected i.p. to four different experimental groups and respective controls of unanesthetized male Sprague-Dawley rats. Exhaled 14CO2 was completely collected during 4 h and peak exhalation rate and fraction of dose recovered were calculated. 1/3 hepatectomy affected 14CO2 exhalation to a limited extent, decreasing solely peak exhalation rate (p < 0.05 compared to sham-operated controls). 2/3 hepatectomy, on the other hand, resulted in significant reduction (p < 0.01) in both peak exhalation rate (by 59%) and fraction of dose recovered (by 47%), that were proportionate to the loss of liver mass (59%). End-to-side portocaval shunt led to the well-documented hepatic "atrophy", liver weight being diminished on average to 50% within 2 weeks of surgery; however, reductions in peak exhalation rate (by 75%) and fraction of dose recovered (by 64%) were even more pronounced. Finally, 48 h bile duct ligation was equivalent to "functional 2/3 hepatectomy", peak exhalation rate (by 65%) and fraction of dose recovered (by 56%) being markedly diminished despite increased liver weight. These results indicate that 14CO2 exhalation curves following administration of specifically labelled caffeine are quantitative indicators of acute or chronic loss of functioning liver mass. In addition, the 3-demethylation pathway appears to be particularly sensitive to the inhibitory effects of cholestasis on microsomal function.
Animals↗
Colchicine does not inhibit secretin-induced choleresis in rats exhibiting hyperplasia of bile ductules: evidence against a pivotal role of exocytic vesicle insertion.
Based on studies in the pig, secretin choleresis has been proposed to be initiated by colchicine-inhibitable, exocytic insertion into the basolateral cholangiocyte membrane of intracytoplasmatic vesicles containing a H+ ATPase. Formal proof of this hypothesis in the intact liver of other species, however, is lacking. The effect of the microtubule inhibitor colchicine on the ductular bile formation and HCO3- secretion induced by secretin was, therefore, explored in a secretin-responsive rat model characterized by marked hyperplasia of bile ductules. While colchicine pretreatment significantly decreased basal bile flow from 142.1 +/- 8.8 to 83.4 +/- 8.2 microliters.min-1.kg-1 (p < 0.001) and basal biliary erythritol clearance from 112.7 +/- 6.3 to 69.9 +/- 7.0 microliters.min-1.kg-1 (p < 0.05), it did not significantly affect basal biliary [HCO3-], nor basal biliary bile acid output. Moreover, colchicine did not alter the effects of secretin. Thus, the secretin-induced increments in bile flow, biliary [HCO3-] and biliary HCO3- output averaged 58.2 +/- 13.6 microliters.min-1.kg-1, 16.6 +/- 3.1 mM and 5.3 +/- 1.4 mumol.min-1.kg-1 in vehicle-pretreated controls and 78.4 +/- 12.0 microliters.min-1.kg-1, 16.1 +/- 2.7 mM and 5.1 +/- 0.5 mumol.min-1.kg-1 in colchicine-pretreated animals (all p values = n.s.), respectively. This suggests that, at least in the rat model used, microtubule-dependent mechanisms are involved in basal, bile acid independent canalicular, but not in secretin-induced ductular, bile formation. Inasmuch as microtubule-dependent mechanisms are required for vesicle movement, this argues strongly against an absolute requirement for exocytic vesicle insertion in the ductular choleresis induced by secretin.
Animals↗
Liver function tests.
For optimal timing of liver transplantation and for the evaluation of new pharmacotherapeutic options, objective modalities for estimating the liver's functional reserve and prognosis in an individual patient are highly desirable. In the past a number of tests and several scoring systems have been proposed and validated to varying degrees for this purpose. The issues still to be clarified include: (1) any observed prognostic value of individual quantitative function tests and of scoring systems must be validated in independent, large enough and well defined patient populations; (2) it must be prospectively defined which (serially performed) quantitative test(s) add(s) prognostic information for the individual patient to the survival estimates defined by the more universally available scores and in which disease state(s); and (3) existing scoring systems must be validated, or new ones developed, that allow follow-up data to be used in order to adapt the original prognosis estimate to the evolution of the disease, e.g. during therapy.
Humans↗
[Does the primary disease recur following liver transplantation?].
A number of underlying diseases may recur after orthotopic liver transplantation. While the recurrence of cholestatic diseases such as primary biliary cirrhosis and primary sclerosing cholangitis is still debated, and occurs, if at all, rarely and late after transplantation, the chronic viral hepatitides and the liver tumors recur frequently and in general early after grafting. Except for hepatitis B and tumor recurrence, recurrent diseases have rarely an impact on survival and/or quality of life in medium terms. The frequency of the often fatal hepatitis-B reinfection can be minimized by passive immunoprophylaxis and appropriate patient selection, that of tumor recurrence by thorough patient selection. Relapses occur only rarely after transplantation for post-alcoholic cirrhosis, provided stringent selection criteria, including a period of documented sobriety > or = 6 month prior to transplantation, are applied. Thus, except for chronic hepatitis B with ongoing viral replication and most liver cancers, the possibility of recurrent disease is not a contraindication to liver transplantation.
Cholangitis, Sclerosing↗