Effect of blood letting on serum aminotransferase levels of patients with chronic hepatitis C and iron overload

We found in the Ca2+ channel alpha1C subunit gene a new repetitive element of three paired exon 45/46-related sequences. We also identified a new exon 45/46-related sequence in the human genome and mapped it by fluorescence in situ hybridization to the 12p11.2 and 12p13.2-p13.1 bands. These positions are not recognized by DNA probes generated from the 5'- and 3'-terminal regions of the alpha1C gene. A possible existence of a new genomic homologue of the alpha1C subunit gene is discussed.     

Hepatitis C virus RNA in serum of blood donors with or without elevated transaminase levels

The pattern of hepatitis C virus (HCV) viremia in blood donors who are positive for antibody to HCV (anti-HCV) according to the level of transaminase activity is unclear. A polymerase chain reaction-based HCV RNA detection method was used to study two clearly defined groups of anti-HCV-positive blood donors with repeatedly normal (n = 27) and elevated (n = 17) alanine aminotransferase (ALT) levels. HCV RNA was detected in only 4 of 27 blood donors with normal ALT values and 15 of 17 with elevated ALT values. These results indicate that anti-HCV-positive blood donors with normal ALT levels constitute a heterogeneous group, as HCV viremia is detectable in only a small proportion of cases. Polymerase chain reaction should be useful in the surveillance of anti-HCV-positive blood donors with normal ALT levels, by identifying those who might benefit from further investigation and treatment.     

Demographic determinants of hepatitis C virus seroprevalence among blood donors

OBJECTIVE: To measure demographic determinants of hepatitis C virus (HCV) seroprevalence among blood donors in the United States. DESIGN: Cross-sectional epidemiological study. SETTING: Five blood centers in different regions of the United States. SUBJECTS: A total of 862,398 consecutive volunteer blood donors with one or more nonautologous donations from March 1992 through December 1993. METHODS: Demographic data collection, serological screening with second-generation anti-HCV enzyme immunoassay, and confirmation with anti-HCV recombinant immunoblot. RESULTS: There were 3126 donors with at least one blood donation confirmed HCV-seropositive, for a crude prevalence of 3.6 per 1000. Age-specific HCV seroprevalence rose from 0.5 per 1000 donors younger than 20 years to a maximum of 6.9 per 1000 in donors aged 30 to 39 years and declined in older age groups. There was interaction between age and educational attainment, with 30- to 49-year-olds with less than a high school diploma at highest risk of HCV infection (odds ratio [OR], 33.0; 95% confidence interval [CI], 23.0 to 47.2 compared with those younger than 30 years with a bachelor's degree or higher degree). Other independent risk factors for HCV seropositivity included male sex (OR, 1.9; 95% CI, 1.8 to 2.1), black race (OR, 1.7; 95% CI, 1.6 to 1.9), Hispanic ethnicity (OR, 1.3; 95% CI, 1.1 to 1.5), previous blood transfusion (OR, 2.8; 95% CI, 2.5 to 3.1), and first/only time donor status (OR, 4.2; 95% CI, 3.9 to 4.5 compared with repeat donors). Seropositivity for human T-lymphotropic virus types I and II, human immunodeficiency virus, or hepatitis B core antigen was highly associated with HCV seropositivity (OR, 10.4; 95% CI, 9.6 to 11.4 for one vs no marker). CONCLUSIONS: Despite a low overall HCV prevalence in blood donors in the United States, there is a marked variation in HCV seroprevalence by demographic subgroup, even after controlling for prior blood transfusion, a recognized risk factor for HCV. Further study of the prevalence of other parenteral risk factors such as past injection drug use among blood donors is needed.     

T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus--positive blood donors without viremia

As the host's immune response may determine the course of hepatitis C virus (HCV) infection, we studied the humoral and cellular immune responses to HCV-related antigens in subjects with different outcomes of HCV infection. Lymphoproliferative responses and circulating antibodies to a panel of HCV core- and E1-related 25-mer peptides were examined in 10 healthy anti-HCV-seropositive blood donors (group A) and in 29 patients with chronic hepatitis C (group B). In addition, cellular recognition of recombinant HCV proteins (core, NS3, NS4A, NS5A, NS5B) were investigated. In group A, stronger T-cell responses were detected against both HCV proteins (core, P = .03; NS4, P = .005; NS5B, P = .03) and peptides. Proliferation was induced by the same peptides in each group, defining at least five distinctive epitopes within core (amino acids [aa] of 20-44, aa 39-63, aa 79-103, aa 118-152 and aa 148-172) and three regions within E1(aa 198-252, aa 308-372, and aa 368-392). Subjects with strong T-cell responses had low or no detectable levels of peptide-specific antibodies, and vice versa. In particular, T-cell responses were more common in group A; B-cell responses were more common in group B. From our data, we conclude that a benign course of HCV infection may be the consequence of the effective activation of T-helper lymphocytes.     

Immunoglobulin M antibody response to hepatitis C virus core protein in patients with chronic hepatitis C

We retrospectively assessed the frequency and clinicopathologic and virologic significance of production of immunoglobulin M (IgM) antibody to hepatitis C virus (HCV) core protein in patients with chronic hepatitis C. Sera from 60 patients with chronic hepatitis C were tested for IgM anti-HCVcore (anti-HCc). Twenty of these patients received ribavirin plus interferon-alpha for 24 weeks, and were classified as sustained, transient, or nonresponders on the basis of alanine aminotransferase levels and the presence of HCV RNA at the end of treatment and 24 weeks later. IgM anti-HCc was detected in 21 patients. There was no correlation between the presence of IgM anti-HCc and clinical features such as sex, age, mode of transmission, serum levels of alanine aminotransferase, HCV genotype, serum HCV titer, or histologic findings. Among the patients who received ribavirin plus interferon-alpha, the mean IgM anti-HCc level before therapy was comparable between sustained (n = 10), transient (n = 8), and nonresponders (n = 2). A statistically significant decrease in IgM anti-HCc response during antiviral therapy was observed in the 18 responders who became negative for serum HCV RNA at the end of therapy. These data suggest that IgM anti-HCc is of limited clinical usefulness as a marker of chronic HCV infection. Serial testing for IgM anti-HCc may provide a marker of antiviral response.     

Association between diabetes and elevated serum alanine aminotransferase activity among Mexican Americans

Elevated activities of serum aminotransferases are a common sign of liver disease and are observed more frequently among diabetics than in the general population. Whether this association is due to confounding factors is unknown. The authors investigated whether diabetes was significantly associated with elevated serum activity of alanine aminotransferase (ALT) after adjustment for factors common to both diabetes and raised ALT. Data from 2,999 men and women aged 20-74 years representative of the Mexican American population of the southwestern United States were obtained from the Hispanic Health and Nutrition Examination Survey (1982-1984). Approximately 6% of men and 2% of women had elevated serum ALT activity (>43 IU/liter). The odds ratio for diabetes as a predictor of elevated ALT was 4.1 (95% confidence interval 2.3-7.6) adjusted for age and sex, which decreased to 3.0 (95% confidence interval 0.92-9.74) after adjustment for age, sex, body mass index, alcohol consumption, and other factors. In addition to diabetes, body mass index was also significantly (p < 0.05) associated with elevated ALT activity. Heavier alcohol consumption and male sex increased the likelihood of elevated ALT, whereas coffee consumption reduced it. Diabetes and liver injury appear to be associated, even with control for factors in common.     

Epidemiologic characteristics of blood donors with antibody to human immunodeficiency virus: Thailand

Clinical decisions should be based on evidence. This paper explores the skills necessary to read critically and evaluate medical literature, and in particular discusses how to appraise a study from a general practice perspective. It outlines the different types of study used in medical literature and the weight that should be attributed to each. The anatomy of a research paper is described indicating the important features to be found in each section of a study; the Introduction, Methods, Results, Discussion and Conclusion (IMRAD) and the essential components, possible problems, and sources of bias that may be found in each section. The need for close examination of the methodology is emphasised, as this determines the quality of the study, with sufficient detail provided in the methods section that the study could be replicated. Sampling and bias are explored in detail and the important features of a measuring instrument are described. Response rates, confounding factors and the use of statistics are also highlighted. The study upon which the research paper is based is usually the best that was possible within resource limitations and, while the evidence should be appraised objectively, the quality of the study should be seen within the context of these limitations.     

The risk of hepatitis C virus infection among blood donors in Osaka, Japan

A 70-year-old male presented with a plasma cell granuloma extending from the extracranial to the intracranial space. Findings of preoperative magnetic resonance imaging and intraoperative observation indicated that the lesion extended from the temporal muscle to the subarachnoid space, penetrating the frontal bone. The subarachnoid lesion was composed of neutrophils indicating the presence of acute or subacute inflammation. The final diagnosis of the resected tumor was plasma cell granuloma. High levels of antibodies against Epstein-Barr (EB) virus in the cerebrospinal fluid and the immunohistochemical demonstration of EB nuclear antigens in the plasma cell granuloma suggested that EB virus infection was associated with the development of plasma cell granuloma in this patient.     

Prevalence and genotype of hepatitis C virus infection in pregnant women and blood donors in Ghana

BACKGROUND: Short stature is one of the features of Turner syndrome and a form of presentation of monosymptomatic celiac disease. METHODS: The recognition of celiac disease in two antiendomysium antibody-positive Turner syndrome girls who did not respond to growth hormone treatment led us to perform as a screening for celiac disease IgA and IgG antigliadin antibodies and antiendomysium antibodies determination in other 35 Turner syndrome patients. Intestinal biopsy was proposed to the antiendomysium antibodies-positive girls; in the former, subtotal villous atrophy was found; in the latter, one parent's consent for intestinal biopsy was not obtained. RESULTS: The prevalence of celiac disease in Turner syndrome patients observed in the present study (8.1 if we consider 3 villous atrophy, 10.8 if we consider 4 antiendomysium antibody-positive) is quite high and seems to indicate that the association of these two disorders could not be coincidental. As to the clinical picture, celiac disease appeared atypical in one case, typical in another one and as a silent form in the third case. Of the 3 cases with villous atrophy on gluten-free diet growth hormone therapy was not effective in two girls, who were older than 16 years, while in the younger patient, detected by the screening, a significant increment of height velocity and height Standard Deviation Score for Chronological Age according to Turner references was observed. CONCLUSIONS: This study suggests that celiac disease can be associated with Turner syndrome and even responsible for a failure of growth hormone therapy. Therefore we propose to perform in Turner syndrome patients antiendomysium antibody determination as a screening followed by intestinal biopsy in positive cases. This would be advisable at least before starting growth hormone treatment.     

Correlation between relative number of circulating low-density hepatitis C virus particles and disease activity in patients with chronic hepatitis C

Hepatitis C virus (HCV) circulates as particles having differing buoyant densities. Changes in the relative proportions of virus particles of different densities were examined in 19 patients with chronic hepatitis C: 6 without (group A) and 13 with (group B) abnormal serum alanine aminotransferase (ALT) levels. High- and low-density virus particles were separated by differential flotation centrifugation. The numbers of high-density particles consistently exceeded that of low-density particles in all patients in group A, whereas the titers of both types of particles were the same at least once in 7 of 10 patients sampled at two time points in group B. The ALT level significantly increased <2 months later (P < 0.05) when the titers of both types of particles were the same in patients in group B. Thus, we found a correlation between the relative numbers of circulating low-density HCV particles and disease activity in chronic hepatitis C patients.     

Correlation between soluble transferrin receptor and serum ferritin levels following bone marrow transplantation for thalassemia

This study analyzes the serum transferrin receptor (sTfR) levels in a series of 230 ex-thalassemics with a follow-up of 1 to 9 years after bone marrow transplantation (BMT) for homozygous beta thalassemia. Ex-thalassemics are individuals, cured of homozygous beta thalassemia by BMT, who maintain different degrees of iron overload acquired during the pretransplant period. Both in experimental and clinical conditions, sTfR concentrations have been shown to be a quantitative measure of body iron status. This study was carried out to assess whether the level of sTfR may be of help in determining the extent of iron overload in ex-thalassemics. Patients who received the marrow from their HLA-identical sibling donor heterozygous for beta thalassemia, namely heterozygous ex-thalassemics, displayed significantly higher levels of sTfR than patients transplanted from their normal sibling donors (normal ex-thalassemics). This finding suggests that increased erythropoiesis, albeit in part ineffective in heterozygous ex-thalassemics, is responsible for the sTfR increment. Both heterozygous and normal ex-thalassemics had significant lower sTfR levels than their heterozygous (p < 0.003) or normal (p < 0.0001) donors, respectively. These differences may be ascribed to the presence of iron overload in ex-thalassemics in comparison to their normal or heterozygous donors who did not present excess of iron in the body. A significant inverse correlation between sTfR and serum ferritin levels (r = -0.54, p < 0.0001) was found when normal ex-thalassemics were considered. In heterozygous ex-thalassemics, the lack of correlation between these two parameters may be explained by the enhanced erythropoietic activity of individuals with thalassemic trait. These results suggest that the level of sTfR may be a useful indicator of iron overload in normal ex-thalassemics.     

Use of overlapping synthetic peptides to characterize samples from blood donors with indeterminate results to hepatitis C virus core antigen

The diagnosis of occult fractures of the scaphoid bone is even more challenging than that of conventional fractures of the scaphoid. This study aimed to compare prospectively the gold standard method (plain radiographs in four projections, after about 14 days) and the primary findings with direct magnification radiography (DIMA) and magnetic resonance imaging (MRI). Primary MRI showed much higher diagnostic power than plain radiography at 10-14 days in occult scaphoid fractures and in detection of associated carpal injuries. This may lead to a decreasing time of disease. DIMA was inferior in detecting occult fractures of the scaphoid.     

Chronic hepatitis C with normal aminotransferase levels: a clinical histologic study

OBJECTIVE: To define chronic hepatitis C virus (HCV) infection among patients with persistently normal aminotransferase levels (PNAL). DESIGN: Retrospective chart review of all patients encountered during 1-yr with positive hepatitis C antibody (anti-C100-3 ELISA), no alternative cause for their liver disease and PNAL for 6 or more consecutive months prebiopsy. Blinded review of liver histology. SETTING: Outpatient hepatology clinics of two academic centers. PATIENTS: Fifty patients with PNAL among 303 with hepatitis C. MEASUREMENTS: Epidemiologic profiles, reasons for seroscreening and confirmatory analyses were tabulated. Histology was reviewed and grading of inflammatory activity and stage of fibrosis was determined by protocol. RESULTS: Among 50 patients with PNAL, 35 (70%) were female, 34 (68%) had parenterally acquired HCV, 44 (88%) abstained (> 2 yr) from ethanol, all were HIV-negative and none pharmacologically immunosuppressed. HCV infection was uniformly confirmed by RIBA II or HCV-RNA assay. The mean level of HCV-RNA by quantitative PCR was 3.79 x 10(5) copies/ml (range, 500 to 1.8 x 10(6) copies/ ml) and by B-DNA, 53 x 10(5) copies/ml (range, 3.5-230 x 10(5) copies/ml). Traditional histoevaluation yielded chronic hepatitis ("active", n = 15; "persistent", n = 25), cirrhosis (n = 7), and normal histology (n = 3). Blinded protocol review of histology (inflammatory grade/fibrotic stage) revealed 0/0 (n = 4), 1/0 (n = 6), 2/0 (n = 17), 2/1 (n = 3), 2/4 (n = 1), 3/0 (n = 2), 3/1 (n = 6), 3/2 (n = 2), and 3/3 (n = 9). CONCLUSIONS: In chronic HCV infection, active inflammation, fibrosis, and variable circulating HCV-RNA levels may coexist with PNAL, particularly among female nondrinkers. Asymptomatic carriers with normal histology comprise 6 to 8% of chronic hepatitis C with PNAL. Management guidelines for this group of patients need to be developed.     

Effects of interferon-alpha on serum hepatitis C virus in patients with chronic hepatitis C

Interferon is beneficial in some patients with chronic hepatitis C. To assess the efficacy of interferon, we used the polymerase chain reaction (PCR) to measure HCV RNA in serial serum samples from 13 chronic hepatitis C patients who were treated with interferon-alpha. Serum alanine aminotransferase (ALT) values normalized in association with the disappearance of serum HCV RNA in nine cases during the therapy. Serum HCV remained negative after the therapy in the three patients who had no relapse, while serum HCV RNA reappeared in the six patients with elevation of ALT values. The persistence of normal ALT levels appears to be correlated with the clearance of the serum HCV. There were two patients whose ALT became normal immediately after the cessation of interferon. Serum HCV was detectable at the end of treatment when serum ALT was elevated, and thereafter serum HCV disappeared. This result suggests an immunomodulatory effect of interferon in the clearance of HCV in some cases. Furthermore, the semiquantitative PCR assay showed that all five patients in whom ALT values were normal at the end of follow-up without detectable serum HCV genome had lower HCV titers in the pretreatment sera than the other eight patients. The detection of HCV RNA by the PCR assay is useful in determining the efficacy of interferon and its mechanisms.     

Study of serum alanine-aminotransferase levels in blood donors in Spain

BACKGROUND AND OBJECTIVE: Serum alanine-aminotransferase (ALT) is being used as a surrogate test for preventing post-transfusion viral hepatitis. However, ALT elevation is influenced by many factors. We have studied ALT levels in 1,036 consecutive blood donors to determine their association with gender, obesity, and hepatitis virus infection markers. DESIGN AND METHODS: In each donation aspartate-aminotransferase (AST), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (gamma GT) activity were also determined and body mass index (BMI) was calculated. RESULTS: Five hundred seventy-nine men and 457 women donated blood; ALT activity was 25.3 +/- 14.5 IU/L (mean +/- SD) for men and 16.3 +/- 7.9 IU/L for women (p < or = 0.0005). The upper normal value for men was 56 IU/L and 34 IU/L for women. On applying this value to the study group 4.8% of the men and 2% of the women had values greater than the cutoff. Among the men with increased ALT levels, 53.5% had a BMI > 27, 7.1% also had an increased level of GGT and 7.1% had increased levels of AST and LDH. None of them were HBsAg nor anti-HCV positive. Among the women with increased ALT, 33.3% had BMI > 27, 33.3% had increased levels of LDH and AST, and 11.1% were anti-HCV positive (only 1 donor). INTERPRETATION AND CONCLUSIONS: It seems clear that different cutoff values should be considered for men and women. Factors such as obesity, may account for more than 50% of the cases with increased ALT values, indicating the low specificity of the test.