Biomedical subjects
Publications and source records attributed to Wolfgang Jessner.
We observed acute HBV superinfection on chronic HCV genotype 1 infection in a 29-y-old injection drug user. On presentation HCV-RNA was already negative and remained so for at least 7 months thereafter. We speculate that clearance of HCV-HBV coinfected cells by HBV-specific immunity might be a mechanism of HCV eradication.
BACKGROUND & AIMS: A 5-fold increase of hepatic copper concentration is considered as the best available test for diagnosis of hepatic Wilson's disease (WD). However, the sensitivity and specificity of this test have never been fully investigated. METHODS: Copper content was measured by flame atomic absorption spectroscopy in 114 liver biopsies obtained at diagnosis of WD, in 219 patients with noncholestatic liver diseases (including 144 with chronic hepatitis C and 44 with nonalcoholic fatty liver disease), and in 26 without evidence of liver disease. RESULTS: Liver copper content was >250 microg/g in 95 WD patients (83.3%), between 50 and 250 microg/g in 15, and below 50 microg/g in 4. It did not correlate with age (r(2) = .003), the grade of fibrosis, or the presence of stainable copper. Liver copper content was >250 or between 50 and 250 microg/g in 3 (1.4%) and 20 (9.1%) of 219 patients with noncholestatic liver diseases, respectively. By lowering the cutoff from 250 to 75 microg/g, the sensitivity of liver copper content to diagnose WD increased from 83.3% (95% confidence interval, 75.2%-89.6%) to 96.5% (91.3%-99.1%), but the specificity decreased from 98.6% (96.0%-99.7%) to 95.4% (91.8%-97.8%). CONCLUSIONS: There is no gold standard for the diagnosis of WD. Liver copper content is a useful parameter, but a value below 250 microg/g does not exclude WD. Diagnosis requires the combination of a variety of clinical and biochemical tests.
There is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-alpha plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-alpha plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n = 67), breakthroughs (n = 16) and relapsers (n = 19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-alpha2a 6 MU daily, ribavirin 800-1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-alpha2a 6 MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/ 102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). On-treatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p < 0.05; week 48: 46% vs. 16%, p < 0.01) but no such difference was found for sustained virological response (20% vs. 12%, NS). In conclusion, triple combination treatment with daily interferon-alpha plus ribavirin plus amantadine for 3 months can induce virological response in a considerable number of nonresponders/relapsers to previous dual combination treatment, but the sustained virological response rate remains low.
BACKGROUND/AIMS: Iron overload is common among patients with chronic hepatitis C (CHC). In this study the role of hepatic iron concentration (HIC) and serum iron parameters was assessed to determine response to standard and pegylated interferon (IFN)/ribavirin combination therapy in patients with CHC. METHODS: Liver biopsies were obtained from 169 IFN-naïve patients (m=115, f=54, age: 40.8+/-10.7) with CHC. 140 patients were treated with standard IFN/ribavirin, 29 patients with pegylated-IFN/ribavirin. Biopsy specimens were evaluated according to the DiBisceglie scoring system and iron grading. HIC was determined by atomic absorption spectroscopy. Ferritin and transferrin saturation and presence of HFE-C282Y and H63D gene mutations were determined at baseline. RESULTS: Nonresponders to combination therapy had higher serum ferritin levels at baseline (p<0.01). There was no difference of HIC, transferrin saturation levels, and the HFE-mutation status between responders and nonresponders. Logistic regression analysis revealed serum ferritin as an independent predictor of response. HIC correlated with the DiBisceglie score (r=0.352, p<0.001), iron grading (r=0.352, p<0.001) and serum ferritin (r=0.335, P<0.001). CONCLUSIONS: Pretreatment liver iron concentration does not predict response to combination therapy in patients with CHC. In contrast, high baseline serum ferritin levels are predictors of poor response to antiviral therapy.
BACKGROUND: Sudden hearing loss has been reported on standard interferon (IFN)-alpha2 therapy. This is the first report on the occurrence of sudden hearing loss in six cases of chronic hepatitis C in temporal relation to treatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy. Three patients were treated in an ongoing randomized placebo-controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 microg PEG-IFN alpha2a (PEGASYS, Roche, Basel, CH)/wk and 1-1.2 g ribavirin/d (COPEGUS, Roche, Nutley, USA) in de novo patients infected with HCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 wk of treatment, respectively. CONCLUSIONS: Sudden hearing loss may occur in about 1% of patients on PEG-IFN/ribavirin combination therapy. This rate was not different to that observed in an untreated population. Possible mechanisms involved include direct ototoxicity of IFN, autoimmunity, and hematological changes. In contrast to published cases on auditory disability due to standard IFN, hearing loss did not fully resolve after discontinuation of therapy with PEG-IFN. On the other hand, symptoms did not worsen on continued treatment. Therefore, the decision whether to continue or to stop the treatment when signs of ototoxicity appear is based on the clinical judgment of the treating physician.
BACKGROUND/AIMS: Initial high-dose interferon-alpha induction therapy in combination with ribavirin improves sustained response rates in treatment-naïve patients. This prospective, randomized, controlled study tested whether non-responders or relapsers to interferon monotherapy also benefit from induction therapy. METHODS: Patients with chronic hepatitis C who had not responded to (n=75) or relapsed (n=80) after previous interferon therapy were randomized to receive three different interferon doses during the first 14 weeks of therapy (A: 10 MU IntronA/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; B:5 MU/d for 14 weeks; C: 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. All patients received 1-1.2 g ribavirin/day throughout the whole study. RESULTS: The rates of viral clearance at any time on treatment were similar in all groups. Sustained response rates were also not different among the groups in interferon nonresponders (A 32%, B 29%, C 31%) and relapsers (A 64%, B 68%, C 71%), respectively, as well as in patients with different genotypes. As expected, sustained response rates were higher in patients with genotype non-1 than in those with genotype 1. CONCLUSION: High-dose induction therapy does not improve the outcome of interferon/ribavirin therapy in interferon nonresponders or relapsers.
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BACKGROUND/AIMS: Central nervous system abnormalities such as fatigue and depression occur more frequently in chronic hepatitis C virus (HCV) infection than in many other causes of chronic liver disease. The finding that fatigue is unrelated to activity of hepatitis or mode of infection could indicate an independent effect of HCV on brain function. This study tested the hypothesis of a subclinical cognitive dysfunction in HCV-infected patients. METHODS: One-hundred untreated HCV-RNA positive biopsy-proven patients were investigated by P300 event-related potentials, a sensitive electrophysiologic test of cognitive processing. Health-related quality of life and fatigue were assessed using the SF-36 questionnaire and the Fatigue Impact Scale, respectively. RESULTS: Cognitive brain function was subclinically impaired in the cohort of HCV-infected patients as indicated by significantly prolonged P300 latencies (P=0.01 for comparison to matched healthy subjects) and reduced P300 amplitudes (P<0.001, respectively). Seventeen of the 100 HCV-infected patients had P300 latencies outside the age-adjusted normal range. Abnormal P300 characteristics were not related to the degree of histologic or biochemical activity of hepatitis, severity of fatigue or mental health impairment. CONCLUSIONS: This study demonstrates that patients with HCV infection showed a slight but significant neurocognitive impairment, possibly indicating a further extrahepatic manifestation of chronic hepatitis C.
Viral dynamics is a concept analyzing the time course of treatment-induced changes in blood virion concentration (kinetics) to derive conclusions of where, when and how in the living organism virions are produced or eliminated. Originally applied to human immunodeficiency virus type 1 and hepatitis B virus, it has elucidated mechanisms of antiviral therapy in hepatitis C virus infection as well. This review summarizes key aspects of mathematical modeling as well as important clinical applications, namely induction therapy and prediction of virologic response to treatment. Furthermore, limitations of currently available quantitative assays will be discussed.
BACKGROUND & AIMS: Treatment of chronic hepatitis C with interferon (IFN)-alpha often has hematotoxic effects. We evaluated the effects of acute vs. chronic and standard vs. pegylated IFN-alpha on hematopoiesis. METHODS: We studied hematopoiesis in 46 patients with chronic hepatitis C receiving single high-dose IN-Falpha2b followed by daily dose standard or weekly pegylated IFN before combination antiviral therapy. RESULTS: Single high-dose therapy resulted in a significant drop in hemoglobin (HB), leukocytes, and platelet count. Although platelets, stimulated by a significant increase in thrombopoietin (TPO), and leukocytes recovered quickly, HB remained below baseline for 7 days. Daily standard or weekly pegylated IFN-alpha leads to a more pronounced drop in all 3 lineages with concomitant increases in TPO and erythropoietin (EPO). No difference was observed between standard and pegylated IFN, except for HB, which fell more during pegylated IFN therapy. Consecutive combination antiviral therapy aggravated the anemia but not the drop in leukocytes or thrombocytes. CONCLUSIONS: The drop in all 3 hematopoietic lineages through IFN-alpha treatment, high-dose standard, standard daily dose, or pegylated, is caused by a combination of bone marrow inhibition and probably some other rapid acting mechanisms. Hematopoietic growth factors are increased as a consequence but cannot overcome the bone marrow suppression.
In view of the occurrence of hepatobiliary disorders in cystic fibrosis (CF) this study addresses the role of the cystic fibrosis transmembrane conductance regulator (CFTR) and of Ca(2+)-activated Cl(-) channels in promoting HCO3- secretion in bile ductular cells. Human cholangiocytes were isolated from control livers and from 1 patient with CF (DeltaF508/G542X mutations). Single channel and whole cell currents were analyzed by patch clamp techniques, and HCO3- secretion was determined by fluorometric analysis of the rate of recovery of intracellular pH following alkaline loading. In control cholangiocytes, both cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) catalytic subunit, activated CFTR Cl(-) channels that exhibited a nonrectifying conductance of 8 pS and appeared in clusters. Activation of Cl(-) current by cAMP was associated with an increase in the rate of HCO3- secretion. The basal rate of HCO3- secretion was lower in CF than in control cholangiocytes. In both control and CF cholangiocytes, raising intracellular Ca(2+) concentrations with ionomycin led to a parallel activation of Cl(-) current and HCO3- secretion. Consistent with reports that premature stop codon mutations (class I; e.g., G542X) can be read over by treatment with aminoglycoside antibiotics, exposure of CF cholangiocytes to gentamicin restored activation by cAMP of Cl(-) current and HCO3- secretion. The observation that activation of Ca(2+)-dependent Cl(-) channels can substitute for cystic fibrosis transmembrane conductance regulator (CFTR) in supporting HCO3- secretion and the efficacy of gentamicin in restoring CFTR function and HCO3- secretion in class I mutations are of potential clinical interest.
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