Hepatitis C virus infection among health care workers.
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Health Personnel↗
Biomedical subjects
G L Davis
Publications and source records attributed to G L Davis.
Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Hepatitis Interventional Therapy Group.
OBJECTIVE: To 1) verify the validity of a new line probe assay for hepatitis C virus (HCV) genotyping and 2) determine the distribution of HCV genotypes and the association between HCV genotype and clinical variables in patients with chronic hepatitis C seen in tertiary referral centers in the United States. DESIGN: Retrospective cross-sectional analysis. PATIENTS: 438 patients with chronic hepatitis C from 10 tertiary referral centers. MEASUREMENTS: The validity of the line probe assay was first verified against a panel of serum specimens that had previously been characterized by six different HCV genotyping methods. Specimens from all 438 patients were then genotyped using this line probe assay. The associations between HCV genotype and clinical variables were examined using analysis of variance. Pairwise testing was used when the F test showed a statistically significant difference. Nonparametric alternatives were used for variables for which normality could not be assumed. RESULTS: The line probe assay was quick and reproducible, and it showed good concordance with other tests. In our sample, the proportions of patients with HCV types 1, 2, 3, and 4 were 71.5%, 13.5%, 5.5%, and 1.1%, respectively. Subtypes 1a and 1b were seen in approximately equal proportions of patients with HCV type 1. Mixed infection was detected in 3.7% of specimens, and 4.8% of specimens either had negative results on polymerase chain reaction or could not be typed. A higher proportion of patients with HCV type 1 than of patients with HCV-type 1 had acquired HCV through transfusion of blood products (50% compared with 25%; P < 0.001). Patients with HCV type 1 also had a longer estimated duration of infection compared with patients with HCV type 3 (P = 0.004) and type 4 (P = 0.049). Disease activity did not differ among patients infected with HCV types 1, 2, or 3. Levels of viremia were similar in patients with HCV types 1, 2, or 3, but patients with HCV type 4 had a lower level of viremia than did patients with HCV type 1 (P = 0.047). CONCLUSIONS: The line probe assay can be used in patients with chronic HCV infection in the United States. In patients with chronic hepatitis C referred to tertiary centers in the United States, type 1 is the most common HCV genotype. Disease activity and viremia levels do not differ among patients chronically infected with HCV types 1, 2, or 3.
Adolescent↗
Breakdown of blood pressure and body fluid homeostasis in heart transplant recipients.
OBJECTIVES: This study was designed to investigate disturbances in arterial blood pressure and body fluid homeostasis in stable heart transplant recipients. BACKGROUND: Hypertension and fluid retention frequently complicate heart transplantation. METHODS: Blood pressure, renal and endocrine responses to acute volume expansion were compared in 10 heart transplant recipients (57 +/- 9 years old [mean +/- SD]) 20 +/- 5 months after transplantation, 6 liver transplant recipients receiving similar doses of cyclosporine (cyclosporine control group) and 7 normal volunteers (normal control subjects). After 3 days of a constant diet containing 87 mEq/24 h of sodium, 0.154 mol/liter saline was infused at 8 ml/kg per h for 4 h. Blood pressure and plasma vasopressin, angiotensin II, aldosterone, atrial natiuretic peptide and renin activity levels were determined before and at 30, 60, 120 and 240 min during the infusion. Urine was collected at 2 and 4 h. Blood pressure, fluid balance hormones and renal function were monitored for 48 h after the infusion. RESULTS: Blood pressure did not change in the two control groups but increased in the heart transplant recipients (+15 +/- 8/8 +/- 5 mm Hg) and remained elevated for 48 h (p < or = 0.05). Urine flow and urinary sodium excretion increased abruptly in the control groups sufficient to account for elimination of 86 +/- 9% of the sodium load by 48 h; the increases were blunted (p < or = 0.05) and delayed in the heart transplant recipients, resulting in elimination of only 51 +/- 13% of the sodium load. Saline infusion suppressed vasopressin, renin activity, angiotensin II and aldosterone in the two control groups (p < or = 0.05) but not in the heart transplant recipients. Heart transplant recipients had elevated atrial natriuretic peptide levels at baseline (p < or = 0.05), but relative increases during the infusion were similar to those in both control groups. CONCLUSIONS: Blood pressure in heart transplant recipients is salt sensitive. These patients have a blunted diuretic and natriuretic response to volume expansion that may be mediated by a failure to reflexly suppress fluid regulatory hormones. These defects in blood pressure and fluid homeostasis were not seen in liver transplant recipients receiving cyclosporine and therefore cannot be attributed to cyclosporine alone. Abnormal cardiorenal neuroendocrine reflexes, secondary to cardiac denervation, may contribute to salt-sensitive hypertension and fluid retention in heart transplant recipients.
Angiotensin II↗
Treatment of unresectable hepatocellular carcinoma.
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Carcinoma, Hepatocellular↗
Significance of hepatic expression of hepatitis C viral antigens in chronic hepatitis C.
To determine the significance of hepatic expression of hepatitis C viral (HCV) antigens, HCV core and NS4 antigens were detected by immunohistochemistry in 46 patients with chronic HCV infection. Serum HCV RNA was quantitated by branched DNA assay in 41 and HCV genotype determined in 30 patients. HCV core and NS4 antigens were detected exclusively in the cytoplasm of hepatocytes in 83% and 61% of patients, respectively. There was no correlation between the expression of HCV antigens and clinical, biochemical, histological parameters and HCV genotype. Hepatic expression of HCV antigens was positively associated with serum HCV-RNA levels (P < 0.02). At the end of interferon-alpha (IFN) therapy, expression of HCV antigens remained either unchanged or decreased in 11/12 patients studied (undetectable in all four patients who had complete and sustained response). We conclude that hepatic expression of HCV core and NS4 antigens parallels serum HCV-RNA levels and IFN therapy reduces hepatic expression of these viral antigens.
Female↗
Relationship between the presence of circulating anti-GOR and hepatitis C viremia/genotype.
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Genotype↗
alpha-Glutathione S-transferase as a marker of hepatocellular damage in chronic hepatitis C virus infection.
alpha-Glutathione S-transferase (alpha GST) may be a good serologic marker of hepatocellular damage because of its low molecular weight, uniform hepatic distribution, high cytosolic concentration, and short half-life. To determine the clinical utility of alpha GST in patients with chronic hepatitis C virus (HCV) infection, serum alpha GST levels were measured in 96 patients with chronic HCV infection, of whom 47 subsequently underwent interferon-alpha therapy. Patients were simultaneously evaluated with conventional liver biochemistry, serum HCV RNA levels, and liver histology. Different methods of serum collection did not affect alpha GST values, indicating that this was a stable serum marker. In 93% of patients with chronic HCV infection, alpha GST was elevated and showed an excellent correlation with serum aminotransferases. Histologic analysis revealed a correlation of alpha GST with both lobular inflammation and bile duct lesions. There was no correlation between serum alpha GST levels and the demographic features, mode of transmission, virologic, other histologic parameters, or subsequent response to interferon-alpha. During serial monitoring in patients undergoing interferon-alpha therapy, elevation of serum alpha GST correlated with biochemical relapse and in some patients virologic relapse in the presence of normal liver biochemistry. alpha GST was persistently elevated in all nonresponders. Four of six of those patients who responded completely followed by early relapse had elevated alpha GST intermittently or continuously during therapy despite normalization of serum aminotransferases. Two of five of those with a complete and sustained response had elevated alpha GST during treatment and follow-up, and both were also seropositive for HCV RNA during follow-up. These data demonstrate that alpha GST is a stable marker, has similar diagnostic utility as serum aminotransferases, and may have a role in the monitoring of patients undergoing interferon-alpha therapy.
Adult↗
Application of six hepatitis C virus genotyping systems to sera from chronic hepatitis C patients in the United States.
Serum samples from 139 US patients with chronic hepatitis C virus (HCV) infection were studied using six different genotyping systems, including both molecular and serologic methods, to determine the applicability of these approaches and the prevalence of various HCV subtypes. The concordance of genotyping results based on the various systems (except for core polymerase chain reaction genotyping) was good (93.5%). Subtypes 1a and 1b were prevalent (37.4%). Subtypes 2a (2.2%), 2b (8.6%), and 3a (5.8%) were less common. HCV genotypes could not be determined in 3.4%-16.5% of samples depending on the method used. HCV type 2 was associated with greater histologic activity but lower serum HCV RNA levels (P < .05), whereas type 3 was associated with lower serum alanine aminotransferase levels (P < .05). These data demonstrate a high concordance between HCV genotyping systems and provide a foundation for comparison of genotyping data between studies using different systems. HCV types 1a and 1b are both prevalent in the United States.
Adult↗
Plasma glutathione concentration in patients with chronic hepatitis C virus infection.
It has recently been proposed that a depletion of glutathione (GSH) may be a contributing factor to viral persistence and resistance to interferon-alpha (IFN-alpha) therapy in chronic hepatitis C virus (HC) infection. The aim of this study was: (1) to compare plasma GSH levels in patients with chronic HCV infection and normal healthy controls; and (2) to correlate GSH levels with liver histology and serum HCV RNA levels. Twenty-four patients with compensated chronic hepatitis C and 27 healthy subjects were studied. Serum and heparinized plasma were prospectively prepared and frozen within 1 h of collection. Plasma glutathione and glutathione peroxidase (GP) levels were measured spectrophotometrically. The serum HCV RNA level was quantitated by the branched chain DNA signal-amplification assay. Plasma GSH levels were not decreased in patients with chronic HCV infection but were actually greater than in controls (control 1.27 +/- 0.12 micrograms ml-1, HCV 1.62 +/- 0.11 micrograms ml-1, P < 0.05). There was also no difference in plasma GP activity between these two groups (control 0.233 +/- 0.007 U ml-1, HCV 0.230 +/- 0.007 U ml-1). Among the patients with chronic HCV infection, there was no correlation between either plasma GSH or GP levels and the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), serum HCV RNA level, or liver histology. This study demonstrates that chronic HCV infection does not decrease the plasma GSH and GP levels.
Adult↗
Choice of appropriate end points of response to interferon therapy in chronic hepatitis C virus infection.
Current definitions of response to interferon (IFN) depend upon decreasing the serum alanine aminotransferase (ALT) level to normal during therapy. Although this complete response is often associated with loss of detectable hepatitis C virus (HCV) in serum, the frequent occurrence of relapse indicates that eradication of the virus is not achieved. Thus, consideration of more meaningful end points for IFN response is necessary. To begin to define a more effective end point, we recently tested serial serum samples from 15 patients with three different biochemical response patterns (five patients, no response; five, complete response with relapse; five, complete and sustained response) for HCV-RNA by both reverse transcription polymerase chain reaction (RT-PCR) and branched DNA signal amplification assay. In the IFN nonrespondes, HCV-RNA was detected in serum and liver at completion of IFN therapy in all five patients. Similarly, in the complete responders followed by relapse, HCV-RNA was still detected in serum and liver at the end of IFN therapy in four and five patients, respectively, despite complete normalization of serum ALT. In the complete and sustained responders, HCV-RNA was detected in serum and liver at completion of IFN therapy in only one and no patients, respectively. However, all five sustained biochemical responders had virologic relapse detected at one or more time points within 6 months after cessation of IFN therapy despite persistently normal ALT. HCV-RNA remained detectable in serum at the pretreatment level without biochemical abnormalities for a range of 1 1/4 to 3 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic Disease↗
Transplantation of a hepatitis B surface antigen-positive donor liver into a hepatitis B virus-negative recipient.
A critically ill, HBV seronegative girl who received a liver from a HBsAg+ donor is described. Despite HBV Ig prophylaxis, she was seropositive for HBsAg shortly after transplantation. Although the postoperative period was complicated, HBV-related problems were not encountered. Liver dysfunction was noted 7 months after transplantation. At that time, she became anti-HBc IgM-positive, with liver histologic findings suggestive of chronic active hepatitis B. The liver function normalized after a reduction of immunosuppressive therapy and introduction of ciprofloxacin. The patient had low level HBV replication during the entire follow-up period (HBV DNA-positive by PCR only) and sequencing of the virus on 4 occasions revealed only wild-type HBV. She subsequently lost serum HBsAg and HBV DNA (even by PCR) and has remained well 2 years after transplantation.
Base Sequence↗
Hepatocyte proliferation as an indicator of outcome in acute alcoholic hepatitis.
To determine whether clinical outcome in patients with acute alcoholic hepatitis is related to the regenerative capability of the liver, liver biopsy specimens from 25 prospectively recruited patients with acute alcoholic hepatitis were studied for hepatic expression of mRNA for two proliferation markers, proliferating cell nuclear antigen and human histone, and for transforming growth factor alpha (TGF alpha) and TGF beta 1 and hepatocyte growth factor (HGF), which regulate hepatocyte proliferation. Proliferation markers were detected to varying degrees in 0-80% of hepatocytes and occasionally in sinusoidal cells and bile-duct epithelium in 19 patients (76%). Patients who survived for 6 months had greater expression of proliferation markers than those who did not survive (p < 0.01). TGF alpha was detected in hepatocytes and bile-duct epithelium, whereas TGF beta 1 was detected mainly in sinusoidal cells and was associated with perivenular fibrosis. Patients who survived for 6 months had greater expression of TGFs than non-survivors (p < 0.02). HGF was detected in sinusoidal cells in 7 patients and correlated with survival (p < 0.01). These data indicate that hepatocyte proliferation, which is possibly related to the pattern of hepatotrophic factor expression, is a good indicator of outcome in acute alcoholic hepatitis.
Acute Disease↗
Interferon treatment of chronic hepatitis C.
The natural history of chronic hepatitis C is just beginning to be clarified, with its more common course being an insidiously progressive liver disease that often remains clinically inconsequential for many years or even decades. Although chronic hepatitis C progresses histologically, the impact on the clinical well-being of the patient is less evident. Interferon is an effective therapy for this disease because of its antiviral effect on the cytopathic hepatitis C virus, lowering serum alanine aminotransferase (ALT) levels, rather than because of any immune modulatory mechanism. Unfortunately, interferon therapy does not permanently eradicate hepatitis C virus in the majority of patients, and relapse with return of the serum ALT level to the pretreatment range occurs in approximately 70% of responding patients. Other interferon-treated patients continue to be viremic and are not considered to be responders. In addition, not all patients with chronic hepatitis C require treatment. A systematic approach to patient evaluation is necessary to determine the need for treatment, assess treatment response, identify side effects of therapy, and assist in other clinical decisions.
Chronic Disease↗
Acute Streptococcus pneumoniae meningogenic labyrinthitis. An experimental guinea pig model and literature review.
OBJECTIVE: To create an experimental model of Streptococcus pneumoniae type 3 meningogenic labyrinthitis (a leading cause of deafness) similar to that in human disease. DESIGN: Cohort analytic study of guinea pigs that were inoculated intrathecally with varying dilutions of S pneumoniae type 3; the progress of the disease was compared with that in saline solution-inoculated control animals. SUBJECTS: Healthy adult Hartley guinea pigs without clinical evidence of middle ear disease that were conveniently sampled. INTERVENTIONS: Intrathecal inoculation of 10(4) to 10(6) colony-forming units of S pneumoniae type 3 into 13 guinea pigs; signs and symptoms of meningitis/labyrinthitis were observed for 15 days and compared with those in two saline solution-inoculated control animals. MAIN OUTCOME MEASURES: Morbidity--labyrinthitis, meningitis; end point--death. RESULTS: The 10(4) to 10(6) colony-forming units of S pneumoniae type 3 caused inflammation that extended from the meninges to the inner ear via the cochlear aqueduct within 3 days after inoculation; a dose of 10(7) killed animals within 12 hours after inoculation. Three of five animals that were inoculated with a 10(6) dose died 3 days after inoculation; two of three animals that were inoculated with a 10(5) dose lived to 15 days after inoculation. One of two animals that were inoculated with a 10(4) dose did not become infected. Inflammation extended to the middle ear by round-window destruction. Reactive bone formation simulated labyrinthine osteosclerosis. Observers assessed histologic slides "blindly." CONCLUSION: Guinea pigs can survive 15 days after intrathecal inoculation of a 10(5) dose, with morphologic features similar to those in human disease. This is an effective model for this study of meningogenic labyrinthitis.
Acute Disease↗
Detection of hepatitis C virus RNA genome in liver tissue by nonisotopic in situ hybridization.
A rapid technique for the detection of hepatitis C virus (HCV) RNA in liver section using nonisotopic in situ hybridization was described. Only 3 of the 10 patients seropositive for antibody to HCV and HCV RNA had detectable HCV RNA in the hepatocytes (1%, 2%, and 15% of cells positive). No specific signal was detected in sinusoidal, biliary epithelial, and mononuclear cells. The positive hepatocytes were scattered in the liver lobule with occasional clusters. The positive signal was confined to the cytoplasmic compartment. These data support the previous observation of the hepatocyte tropism of HCV.
Adult↗
Detection of hepatitis C viral sequences in formalin-fixed, paraffin-embedded liver tissue: effect of interferon alpha therapy.
To determine the effect of interferon-alpha (IFN) therapy on hepatitis C virus (HCV) in liver, reverse transcription "nested" polymerase chain reaction (RT-PCR) was applied to detect HCV RNA in formalin-fixed, paraffin-embedded liver biopsy specimens obtained before and at the end of IFN therapy in 42 patients with chronic HCV infection. Results were correlated with the clinical and biochemical outcome in 36 cases. Fifteen patients were nonresponders to IFN; 13 patients had a complete response to IFN but relapsed shortly after IFN was stopped (responders who relapsed); and 8 patients showed a complete and sustained response to IFN therapy (sustained responders). Total RNA was extracted using proteinase K digestion and phenol/chloroform/isoamyl alcohol extraction, and HCV RNA was detected by standard RT-PCR using primers from the highly conserved 5' untranslated region. HCV RNA was detected in 41 of the 42 pretreatment specimens. Of the 36 patients with paired posttreatment samples, HCV RNA was detected in all 15 patients who did not respond to IFN and 9 of 13 who responded to IFN but relapsed shortly after IFN was stopped. In contrast, only one of the eight patients who had a sustained response to IFN therapy had HCV RNA detected by RT-PCR (P < 0.04). These data confirm 1) the feasibility of detecting HCV RNA in formalin-fixed, paraffin-embedded tissue from patients with chronic HCV infection, 2) show that sustained response to IFN is associated with loss of liver HCV RNA at the end of IFN therapy, and 3) offer an explanation for recurrence in patients who relapse.
Base Sequence↗
Immunoglobulin M and A antibodies to hepatitis C core antigen in chronic hepatitis C virus infection.
To determine the prevalence and clinical significance of IgM and IgA antibody to hepatitis C virus (HCV) core antigen in chronic HCV infection, sera from 47 patients were tested for immunoglobulin class M (IgM) and immunoglobulin A (IgA) antibody to HCV core antigen by solid-phase enzyme-linked immunoassay using a recombinant core protein (aa1-150). Results were correlated with the clinical, biochemical and histological parameters, serum HCV RNA levels (determined by branched DNA signal amplification assay), and subsequent clinical response to interferon-alpha therapy. IgM anti-HCV core was detected in 11 patients (23.4 percent). There was no correlation between the presence of IgM anti-HCV core and the clinical features (sex, age, mode of acquisition), biochemical parameters (serum ALT, AST, alkaline phosphatase, and albumin level), autoimmune markers [serum globulin levels, anti-nuclear antibody (+ at < 1:80 in 7/47 patients)], serum HCV RNA levels, subsequent response to interferon-alpha therapy, and the histological features. Immunoglobulin A anti-HCV core was not detected in any of the patients. The presence of IgM ant-HCV core in a proportion of patients with chronic HCV infection indicates that the presence of serum IgM anti-HCV core may not be unique to acute HCV infection.
Adult↗
Detection of hepatitis C virus genome in formalin-fixed paraffin-embedded liver tissue by in situ reverse transcription polymerase chain reaction.
Detection of hepatic hepatitis C virus RNA and antigens is difficult since their expression is very low. The technique of in situ reverse transcription polymerase chain reaction (IS-RT-PCR) was developed for the detection and localization of HCV RNA in formalin-fixed paraffin-embedded liver sections. Key steps for achieving a good signal-to-background ratio include appropriate proteolytic digestion, DNase pretreatment, higher Mg2+ concentration, primers from the core region, "hot-start", and between 10-20 cycles of PCR. Using this approach, HCV RNA was detected in the liver in four of the six patients. In those positive samples, the percentage of cells positive for HCV RNA ranges from < 5 to 25%. Using RT-PCR of serum samples and RNA extracted from the corresponding tissue block (10 sections) as the gold standard and sections from four control subjects as negative controls, the sensitivity and specificity of this assay was 4/6 and 4/4, respectively. The specific positive signal was found mainly in the cytoplasm of the hepatocytes and occasionally in mononuclear cells but not in the bile duct epithelium or sinusoidal cells. These positive hepatocytes were scattered in the liver lobules with occasional clustering. These preliminary data confirm the hepatotropic nature of HCV and the localization of HCV RNA is consistent with cytoplasmic replication.
Base Sequence↗