Fulminant hepatitis A in a patient with severe hyperthyroidism: rapid recovery from hepatic coma after plasmapheresis and total thyroidectomy.
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China↗
Biomedical subjects
S Zeuzem
Publications and source records attributed to S Zeuzem.
Perihepatic lymph nodes as a marker of antiviral response in patients with chronic hepatitis C infection.
OBJECTIVE: In patients with chronic hepatitis C, the sonographically determined total perihepatic lymph node volume reflects liver histology and viremia. The aim of this prospective study was to assess whether the response to antiviral therapy is reflected by changes in the total perihepatic lymph node volume. SUBJECTS AND METHODS: In 59 patients with chronic hepatitis C infection. the total perihepatic lymph node volume was assessed using sonography before the initiation of antiviral treatment, at the end of treatment, and at the end of a 6-month follow-up period. Hepatitis C viremia was assessed by reverse transcription-polymerase chain reaction assay at the same time points. Liver biopsy was performed in all patients before therapy and in 40 of the 59 patients 6 months after therapy. RESULTS: At the end of follow-up, the total perihepatic lymph node volume was significantly smaller in the 15 patients with a sustained virologic response than in the 44 patients who failed to respond to treatment (0.5+/-0.3 ml versus 2.0+/-1.2 ml; p<0.0001). In the group of sustained virologic responders, the decline of the perihepatic lymph node volume was associated with an improvement in liver histology. CONCLUSION: Total perihepatic lymph node volume changes according to the antiviral response and leads to progressive normalization of the perihepatic lymph node volume in sustained virologic responders. A decrease in the perihepatic lymph node volume is associated with an improvement in liver histology.
Adult↗
Cystic adrenal lymphangioma: incidental diagnosis on abdominal sonography.
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Adrenal Gland Neoplasms↗
Antiviral effect of human recombinant interleukin-12 in patients infected with hepatitis C virus.
The heterogeneity of hepatitis C virus (HCV) is due to the continuous and high replication rate, the low fidelity of the RNA-dependent RNA polymerase, and the immune surveillance of the host. Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The effect of IL-12 on hepatitis C viremia and the HCV quasispecies population is unknown. In this study, 12 patients (9 males, 3 females; mean age: 44 +/- 11 years), all virological non-responders to previous IFN-alpha treatment, received recombinant human IL-12 s.c. once weekly for 10 weeks stratified to three dose schedules (0.03 microg/kg, 0.1 microg/kg, and 0.5 microg/kg body weight, respectively). Fourteen IFN-alpha non-responders and 14 untreated patients served as age- and sex-matched controls. Serum HCV RNA concentrations and HCV quasispecies distribution were measured serially by quantitative reverse transcription - polymerase chain reaction and single strand conformation polymorphism analysis of the hypervariable region of the second envelope gene, respectively. Serum ALT and median HCV RNA levels before treatment (52.7 +/- 21.7 U/L; 2.6 x 10(6) copies/mL) showed no significant changes during IL-12 treatment (57.3 +/- 58.8 U/L and 3.2 x 10(6) copies/mL, 50.3 +/- 46.2 U/L and 3.1 x 10(6) copies/mL, and 46.8 +/- 35.3 U/L and 3.9 x 10(6) copies/mL at weeks 1, 4, and 10, respectively). Similar results were observed in 14 IFN-alpha non-responders and 14 untreated patients. However, changes in HCV quasispecies occurred in 10/12 (83%) and 9/14 (64%) patients treated with interleukin-12 and interferon-alpha, respectively, but only in 3/14 (21%) untreated subjects (P < 0.003 and P < 0.03). These results imply that interleukin-12 exerts only limited antiviral activity against certain HCV quasispecies in vivo.
Adult↗
Hepatitis C virus kinetics.
The balance of virus production and clearance for untreated patients with chronic hepatitis C virus (HCV) results in a decline of viraemia when initiating active antiviral treatment. During the first phase of interferon-alpha therapy, after a delay of about 8-9 h, the kinetics of the viral load is characterized by a rapid dose-dependent decline. This early response can be observed for almost all patients treated with interferon-alpha. After about 24-48 h, the viral decline enters a second phase of relatively slow exponential decay during the following weeks of therapy. Non-responding patients, however, show constant viraemia or even a rebound during this second phase. The rate of the exponential decline of the viral load in responding patients in this second phase is less sensitive to the dose of interferon-alpha and varies considerably among patients. Furthermore, combination therapy with interferon-alpha plus ribavirin does not significantly improve the initial viral decay, although it may prevent more patients from rebounding. Mathematical modelling of viral dynamics reveals high turnover rates of pre-treatment viral production and clearance, and permits the estimation of in vivo half-lives of a few hours for free HCV virions and of 1-70 days for productively infected cells. Infected cell death rate, which determines the second phase decline slope, is predictive of response to treatment. Current models indicate that the early biphasic viral decline is explained if interferon-alpha partially blocks virion production from infected cells, yet they do not rule out additional antiviral or immunological effects. Therapeutic implications are the advisability of use of frequent (daily) and comparatively high initial doses. In conclusion, kinetic analysis of the viral decay during the first weeks of treatment permits the prediction of response at the end-of-therapy and might help to evaluate new drugs and to optimize therapy.
Antiviral Agents↗
Enzymatic and antisense effects of a specific anti-Ki-ras ribozyme in vitro and in cell culture.
Due to their mode of action, ribozymes show antisense effects in addition to their specific cleavage activity. In the present study we investigated whether a hammerhead ribozyme is capable of cleaving mutated Ki-ras mRNA in a pancreatic carcinoma cell line and whether antisense effects contribute to the activity of the ribozyme. A 2[prime]-O-allyl modified hammerhead ribozyme was designed to cleave specifically the mutated form of the Ki- ras mRNA (GUU motif in codon 12). The activity was monitored by RT-PCR on Ki- ras RNA expression by determination of the relative amount of wild type to mutant Ki-ras mRNA, by 5-bromo-2[prime]-deoxy-uridine incorporation on cell proliferation and by colony formation in soft agar on malignancy in the human pancreatic adenocarcinoma cell line CFPAC-1, which is heterozygous for the Ki-ras mutation. A catalytically inactive ribozyme was used as control to differentiate between antisense and cleavage activity and a ribozyme with random guide sequences as negative control. The catalytically active anti-Ki-ras ribozyme was at least 2-fold more potent in decreasing cellular Ki-ras mRNA levels, inhibiting cell proliferation and colony formation in soft agar than the catalytically inactive ribozyme. The catalytically active anti-Ki-ras ribozyme, but not the catalytically inactive or random ribozyme, increased the ratio of wild type to mutated Ki-ras mRNA in CFPAC-1 cells. In conclusion, both cleavage activity and antisense effects contribute to the activity of the catalytically active anti-Ki-ras hammerhead ribozyme. Specific ribozymes might be useful in the treatment of pancreatic carcinomas containing an oncogenic GTT mutation in codon 12 of the Ki-ras gene.
Enzyme Activation↗
[Interferon-alpha and ribavirin: advances in the therapy of chronic hepatitis C].
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Antiviral Agents↗
A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C.
Interleukin-12 (IL-12) plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. The present open-label, multicenter, dose-escalation phase I/II study was designed to assess tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) in the treatment of chronic hepatitis C. Sixty patients (42 men, 18 women, aged 24-60) were treated with 0.03 microgram/kg (n = 16), 0.1 microgram/kg (n = 14), 0.25 microgram/kg (n = 15), or 0.5 microgram/kg rHuIL-12 (n = 15) for 10 consecutive weeks. rHuIL-12 was generally well tolerated, with 2 patients (3.3%) being withdrawn from treatment for adverse events. Treatment was associated with temporary decreases in neutrophils and lymphocyte counts and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microgram/kg compared with 0.25 microgram/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon gamma (IFN-gamma) were also observed at the highest dose of 0.5 microgram/kg. At the end of treatment hepatitis C virus (HCV) RNA was detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3 of 16 patients of the 0.03-microgram/kg dose group, in 3 of 14 of the 0.10-microgram/kg dose group, in 6 of 15 of the 0.25-microgram/kg dose group, and in 8 of 15 patients of the 0.5-microgram/kg dose group. Although in several cases serum alanine transaminase (ALT) levels decreased either during or after treatment, ALT normalization was observed in only 4 patients at the end of treatment and in 5 patients at the end of follow-up. Significant anti-rHuIL-12 antibody titers were not detectable in any patient. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis C does not appear advantageous in comparison with other currently available treatments.
Adolescent↗
Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy.
BACKGROUND/AIMS: Studies from Japan showed that HCV-1b isolates with at least four amino acid changes within NS5A2209-2248 compared with the prototype sequence HCV-J are more sensitive to interferon than isolates with a prototype sequence. However, the data were not unequivocally confirmed in studies from other geographical areas. These discrepancies may be explained by differences in the prevalence of multiple mutations within the NS5A2209-2248 and/or the treatment efficacy. METHODS: In the present study, we therefore investigated the correlation between NS5A2209-2248 sequences of HCV-1b isolates and sustained virological response in 72 European patients treated with 3x6 MU interferon-a per week with (n = 26) and without (n = 46) ribavirin (1000-1200 mg/day). Serum HCV RNA was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the NS5A2209-2248 region was analyzed by sequencing of PCR products or individual clones. RESULTS: Compared with HCV-1b prototype sequences, 19 patients (26%) had no amino acid changes (prototype), 47 patients (65%) had 1-3 mutations (intermediate type) and six patients (8%) had at least 4 mutations in the NS5A2209-2248 region (mutant type). Nine of the 12 patients with sustained virological response were infected with an intermediate type HCV-1b, the remaining three patients revealed a mutant type HCV-1b. A sustained virological response was achieved in three of four patients with a mutant type HCV-1b treated with interferon-alpha and ribavirin, but in none of the mutant type HCV-1b infected patients treated with interferon-a alone. Quasispecies analysis of HCV in the NS5A2209-2248 region showed only minor heterogeneity of the amino acid sequence. CONCLUSIONS: The prevalence of mutant type HCV-1b isolates in European patients is low. In patients treated with combination therapy interferon-a and ribavirin, a correlation between mutant type HCV-1b isolates and sustained virological response was observed. The discrepancies between previous studies appear to be related to the efficacy of antiviral treatment and to the low prevalence of mutant type HCV-1b isolates in Western countries.
Adult↗
Clinical implications of hepatitis C viral kinetics.
Antiviral treatment of patients with chronic hepatitis C can perturb the steady-state of virus production and clearance. From serial measurements of changes in viremia, kinetic information on the dynamics of hepatitis C virus (HCV) replication can be obtained. After a delay of about 9 h due to interferon-a pharmacokinetics, the decline of viremia in patients treated with interferon-alpha is characterized by a concave shape. In the first phase (day 1) a rapid dose-dependent decline in viral load is observed. The second phase viral decline (> or =day 2) shows a much slower decline with no or less pronounced differences between the applied interferon-alpha schedules. While a first phase decline can be observed in almost all patients treated with interferon-alpha, non-responders typically reveal no further decline of viremia during the second phase. Kinetic analysis showed that combination therapy with interferon-alpha plus ribavirin has no direct synergistic antiviral effect in the initial 4 weeks of treatment of HCV-infected patients with 6 MU IFNalpha three times per week. Calculations revealed a minimum virus production and clearance per day in patients with chronic hepatitis C of approximately 10(10)-10(12) virions per day and an in vivo half-life of the virus in the order of a few hours. The high turnover rates of HCV explain the rapid generation of viral diversity and the opportunity for viral escape from the host immune surveillance and antiviral therapy. The implications derived from HCV kinetics comprise the consideration of more aggressive initial dosing regimens (especially daily doses), the possibility to optimize therapy individually not only according to pretreatment parameters but also according to the initial decline of viral load and the perception that eradication of the virus will rely on the half-life of infected cells.
Antiviral Agents↗
Interferon-alpha improves glucose tolerance in diabetic and non-diabetic patients with HCV-induced liver disease.
This pilot study was initiated to evaluate factors controlling glucose tolerance in patients with hepatitis C virus-induced liver disease before and after therapy with recombinant interferon-alpha (r-INF-alpha). Fifteen patients with histologically and serologically proven hepatitis C infection underwent oral and frequently sampled intravenous glucose tolerance tests (FSIGTT) before and after four months of therapy (6 x 106 U r-INF-alpha, subcutaneously, three times a week). Glucose, insulin and C-peptide data from FSIGTT were analysed using the minimal modeling technique to determine insulin sensitivity, glucose effectiveness and first and second phase insulin secretion. According to the WHO criteria 13 patients, had normal glucose tolerance; diabetes mellitus was diagnosed in 2 patients. In the morning following the last r-INF-alpha injection four months later, insulin sensitivity improved significantly in hepatitis C virus-infected patients with normal glucose tolerance (2.17 +/- 0.37 vs. 6.18 +/- 0.94 10(-4) min(-1) per microU/ml, p < 0.001) and with diabetes mellitus (0.86 to 2.61; 0.46 to 1.06 10(-4) min(-1) per microU/ml). This effect was independent of the extent of fibrosis, virus load before treatment and therapy response. First phase insulin secretion increased in non-diabetic (139.2 +/- 17.1 vs. 200.0 +/- 32.7, p < 0.05) and diabetic patients with HCV infection (55.24 to 118.5; 84.23 to 261.1). Moreover, free fatty acid concentrations in all HCV-infected patients were significantly reduced (0.48 +/- 0.01 vs 0.21 +/- 0.03 mmol/l, p < 0.01). Therapy with recombinant interferon-alpha is associated with an amelioration of glucose tolerance in non-diabetic and diabetic HCV-infected patients.
Adult↗
[Analysis of hepatic echo patterns in chronic hepatitis C].
AIM: Patients with chronic hepatitis C often present a bright echopattern of the liver. Our aim was to examine the relationship of the sonographic echotexture of the liver in relation to the histological findings in patients with chronic hepatitis C without cirrhosis. METHODS: The livers of 68 patients with chronic hepatitis C (40 male, 28 female, age: 39 +/- 9 years) were evaluated by high resolution ultrasound equipment (3.5 and 5 MHz). Histologic specimens were obtained at the same time. Grading and staging was performed according to the histological activity index. 70 healthy subjects (40 male, 30 female, age: 35 +/- 9 years, no histology) were examined as controls. RESULTS: A bright sonographic echotexture of the liver was found in 26/68 (38%) patients with chronic hepatitis C, which correlated with the degree of fatty infiltration in the liver. Other parameters of the histological activity index showed no significant correlation with the echotexture of the liver. Hypoechoic areas in the liver hilus were detected in 24/26 (92%) patients with chronic hepatitis C and a bright echotexture of the liver. In 6/70 (9%) healthy subjects a bright sonographic echotexture could be detected. CONCLUSION: Patients with chronic hepatitis C typically show a bright echotexture of the liver, which correlates mainly with the histological finding of fatty infiltration. A hypoechoic lesion next to the liver hilus is present in almost all patients with bright echotexture of the liver and is a sonographic sign of fatty infiltration of the liver, which might represent an area of less fat content and/or more fibrous tissue which could be due to different vasculature.
Adult↗
Peutz-Jeghers syndrome: molecular analysis of a three-generation kindred with a novel defect in the serine threonine kinase gene STK11.
The Peutz-Jeghers syndrome, phenotypically characterized by mucocutaneous pigmentation and hamartomatous polyposis, is an autosomal dominant disease with variable expression and incomplete penetrance. Moreover, affected patients are at increased risk for gastrointestinal and other malignancies. Recently, a mutated gene encoding abnormal forms of the novel serine threonine kinase STK11 has been identified as a genetic cause of Peutz-Jeghers syndrome. Here, we report the molecular analysis of the STK11 gene in a patient with Peutz-Jeghers syndrome, which in exon 1 revealed a guanine (G) insertion in the 5 G repeat of codons 51-53. The insertion leads to a frameshift with a premature TGA stop codon 324 bp downstream in codon 162, predicting the expression of a truncated protein without kinase activity. This heterozygous germline mutation was also found in the affected father and in one affected sister of the index patient, but not in any phenotypically unaffected family member or in unrelated control subjects. In DNA isolated from microdissected hamartomatous polyps of the index patient, exon 1 of the STK11 gene could not be amplified suggesting that both alleles of STK11 exon 1 were lost in the hamartomatous polyps. Identification of a STK11 gene mutation in an index patient offers the possibility of a predictive diagnosis, and initiation of specific screening programs in the genetically affected kindred.
Adult↗
Photoallergic skin reaction to ribavirin.
A 65-yr-old woman with chronic hepatitis C was treated with three million units interferon-alpha t.i.w. and 1000 mg ribavirin daily. At wk 16 of combination therapy the patient developed an itchy eczematous erythema, partly of urticarial character, which was almost confined to ultraviolet (UV)-exposed sites. Histopathological examination of the skin lesions was consistent with a photoallergic reaction. The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h, a distinct erythema at the UVB irradiated site was found, whereas no reaction was seen with UVA provocation up to a dose of 10 J/cm2. Correspondingly, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm. Ribavirin was stopped, and the cutaneous lesions and pruritus completely disappeared without subsequent hyperpigmentation. This case indicates that ribavirin is a potential photosensitizer for UVB, which may become increasingly relevant in patients with chronic hepatitis C undergoing combination therapy for 6-12 months with interferon-alpha and ribavirin.
Aged↗
Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma.
OBJECTIVE: The detection of increased fluorine-18 fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography (PET) is based on the enhanced glucose metabolism of tumor cells. Because the detection and staging of hepatocellular carcinoma (HCC) in patients with liver cirrhosis can be difficult, we prospectively evaluated the sensitivity of 18F-FDG PET in 14 consecutive patients with HCC. METHODS: Whole body and regional 18F-FDG PET of the liver were obtained. The results were compared with ultrasonography, contrast-enhanced, helical CT, histological grading, p53 protein expression of HCC, and serum alpha-fetoprotein (AFP) level. RESULTS: In 7 patients PET demonstrated increased tumor 18F-FDG uptake, whereas HCC was not distinguishable from nonmalignant liver tissue in 7 other patients. Hepatic lesions were detected by ultrasonography in all patients, whereas only 11 of 14 HCCs could be identified by CT. In 3 patients extrahepatic spread was demonstrated by 18F-FDG PET. Patients with increased tumor 18F-FDG uptake had significantly larger hepatic lesions and higher serum AFP levels than those with normal 18F-FDG uptake. Lesions could be visualized by 18F-FDG PET in 7 of 8 patients with moderately or poorly differentiated HCC, whereas none of the six well-differentiated tumors was detected. Two patients with strong p53 expression demonstrated increased tumor 18F-FDG uptake and extrahepatic metastases. CONCLUSIONS: The sensitivity of 18F-FDG PET for the imaging of HCC is low. Nevertheless, in patients with moderately or poorly differentiated HCC, tumors >5 cm, or with markedly elevated AFP levels 18F-FDG PET may contribute to an effective noninvasive staging.
Adult↗
[Regulated exocytosis: Ca(2+)-sensor in exocrine cells?].
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Carrier Proteins↗
[Sonographic detection of perihepatic lymph nodes: technique and clinical value].
Sonographic detection of perihepatic lymphadenopathy by transabdominal ultrasound is helpful in the diagnosis of acute and chronic liver disease but differentiation between benign inflammatory and malignant disease is not possible. The diagnostic value of perihepatic lymphadenopathy has been evaluated in patients with chronic hepatitis C and primary biliary cirrhosis. In patients with chronic hepatitis C enlargement of perihepatic lymph nodes is associated with viremia and is predictive for the presence of severe inflammatory activity with and without cirrhosis. In retrospective studies it could be shown that patients with chronic hepatitis C without response to antiviral therapy do not normalize the size of perihepatic lymph nodes. Future prospective studies have to evaluate whether successful antiviral therapy together with histological improvement will be reflected in an decline of perihepatic lymph node size. In patients with primary biliary cirrhosis the total perihepatic lymph node volume reflect histological stages, i.e. larger lymph nodes are observed in more advanced disease. The mechanism of portal lymphadenopathy in patients with acute and chronic liver disease is unknown. Viral, bacterial infections, and immunological causes are potential etiopathological factors in periportal lympadenopathy. Malignant causes of perihepatic lymphadenopathy have also to be considered.
Adult↗
Evaluation of rapid microsatellite analysis of paraffin-embedded specimens in screening for hereditary nonpolyposis colorectal cancer.
Length alterations in short repetitive DNA sequences, termed microsatellite instability (MSI), are used as a diagnostic criterion of replication errors caused by various mutations in at least five mismatch repair genes. Therefore, MSI analysis is useful in clinical practice to identify patients with hereditary nonpolyposis colorectal cancer (HNPCC). MSI can be detected by amplification of microsatellite loci in DNA extracted from paraffin-embedded tumor and corresponding peritumoral specimens after numerous time consuming steps limiting the clinical utilities. Rapid microsatellite analysis, a efficient and rapid DNA extraction technique based on Triton X-100 preincubation, was compared with the conventional DNA extraction for HNPCC screening in colorectal tumor specimens from 12 patients. Five complex and two noncomplex (CA)n microsatellite loci were tested, with use of multicolor fluorescent analysis. MSI and loss of heterozygosity in colorectal tumor samples could equally be assessed with the two DNA preparation methods, whereas the number of initially unsuccessful DNA extractions from paraffin-embedded tissue specimens and overall duration for MSI analysis were significantly reduced when rapid microsatellite analysis was used. A replication error-positive phenotype was detected in 2 of 10 patients with a positive family history for colorectal cancer, and diagnosis of HNPCC was finally confirmed by detection of a specific germline mutation. The described rapid microsatellite analysis is less time consuming and more efficient, and, in general, it reduces the risk of contamination by limiting the number of steps required. Therefore, it might replace current DNA extraction procedures. Furthermore, techniques using fluorescent polymerase chain reaction and semiautomated DNA sequencer allow for precise, observer-independent, and rapid scoring in MSI and loss of heterozygosity assessment. A combination of our rapid DNA extraction method and the use of a highly specific microsatellite marker might improve replication error analysis in HNPCC screening.
Adult↗