M. Michele Manos

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)‐based test which was used. The formerly HPV‐negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV‐negative and a sample of 48 of the 866 cases which were HPV‐positive in the original study. Moreover, 55 of the 66 formerly HPV‐negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR‐negative and ‐positive. Type‐specific E7 PCR for 14 high‐risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV‐negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA‐positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV‐negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0·001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99·7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV‐negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright

Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease

We performed a cross‐sectional study of newly diagnosed cases of nonalcoholic fatty liver disease (NAFLD) identified between December 1998 and December 2000 in the Chronic Liver Disease Surveillance Study. We compared the demographic and clinical features of NAFLD in a racially diverse representative U.S. population (Alameda County, CA). Diagnostic criteria for probable NAFLD were persistent unexplained elevation of serum aminotransferase levels, radiology (ultrasound or computed tomography scan) consistent with fatty liver, and/or two or more of the following: (i) body mass index of 28 kg/m2 or more, (ii) type 2 diabetes, or (iii) hyperlipidemia, in the absence of significant alcohol use. Definite NAFLD cases required histological confirmation. Of the 742 persons with newly diagnosed chronic liver disease, 159 (21.4%) had definite or probable NAFLD. The majority were nonwhite: Hispanics (28%), Asians (18%), African Americans (3%), and other race(s) (6%). African Americans with NAFLD were significantly older than other racial or ethnic groups (P < .001), and in Asians, NAFLD was 3.5 times more common in males than in females (P = .016). Clinical correlates of NAFLD (obesity, hyperlipidemia, diabetes) were similar among racial and ethnic groups, except that body mass index was lower in Asians compared with other groups (P < .001). Compared with the base population (Kaiser Permanente members), Hispanics with NAFLD were overrepresented (28% vs. 10%) and whites were underrepresented (45% vs. 59%). In conclusion, these racial and gender variations may reflect differences in genetic susceptibility to visceral adiposity, including hepatic involvement, and may have implications for the evaluation of persons with the metabolic syndrome. Clinicians need to be aware of the variable presentations of NAFLD in different racial and ethnic groups. (HEPATOLOGY 2005;41:372–379.)

A Prospective Study of Human Papillomavirus (HPV) Type 16 DNA Detection by Polymerase Chain Reaction and Its Association with Acquisition and Persistence of Other HPV Types

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses.

Objective To characterize the relative contributions of the different abnormal Papanicolaou smear cytologic diagnoses in the Bethesda System to the subsequent histologic diagnosis of high-grade cervical neoplasia. Methods A total of 46,009 nonpregnant female members of the Kaiser Permanente Health Plan, Northern California Region, were studied prospectively. The main outcome measures included routine Papanicolaou smear diagnoses and subsequent histologic diagnosis of colposcopically directed cervical tissue specimens. Results Atypical squamous cells of undetermined significance (ASCUS) was the most common abnormal Papanicolaou diagnosis, representing 3.6% of the total number of smears. Of the total number of cases of histologically confirmed high-grade cervical neoplasia present in the population, the largest proportion (38.8%) was in women with smears showing ASCUS. Minimal abnormalities combined (ASCUS, atypical glandular cells of undetermined significance, and low-grade squamous intraepithelial lesion) were coincident with 68.6% of the cases of histologic high-grade cervical neoplasia diagnosed in this routine screening population. Conclusion Recognition of the importance of equivocal and mild Papanicolaou test abnormalities in the subsequent diagnosis of high-grade cervical neoplasia emphasizes the need for accurate and cost-effective triage of the large population of women with minimally abnormal Papanicolaou diagnoses.

Determinants of genital human papillomavirus infection in low-risk women in Portland, Oregon.

OBJECTIVES To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY To investigate risk factors for HPV detection independent of the correlated risk factors for cervical neoplasia in a low-risk population. STUDY DESIGN HPV DNA was assessed among 483 cytologically normal women with no known history of cervical neoplasia. A cervicovaginal lavage was collected for HPV detection and typing using a PCR-based DNA amplification system. Information on risk factors of subjects was obtained through a questionnaire. RESULTS HPV DNA was found in 17.7% of study women. On univariate analysis, factors associated with increasing HPV prevalence included younger age, fewer years of education, lower income, higher lifetime number of sex partners, lower age at first intercourse, nulliparity, oral contraceptive use, and current smoking. After statistical adjustment, we found younger age and higher number of sex partners were strongly and independently associated with higher HPV prevalence. We also observed increased HPV prevalence among women with lower levels of education and lower incomes. CONCLUSION These findings and corroborative data from the companion reports in this issue of the journal support the sexual route of transmission of the virus.

Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center.

OBJECTIVES To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY To investigate risk factors for HPV detection apart from the correlated risk factors for cervical neoplasia. STUDY DESIGN Cervical human papillomavirus (HPV) DNA was assessed in 357 cytologically normal women attending the University of New Mexico student health center. Cervical swab samples were obtained for HPV DNA detection and typing using a PCR-based DNA amplification system. Possible determinants of cervical HPV were examined including age, ethnicity, history of sexually transmitted disease, oral contraceptive use, smoking, age at first intercourse, lifetime number of sex partners, marital status, and history of pregnancy. RESULTS A 44.3% overall prevalence of cervical HPV was observed. On univariate analysis, factors associated with increasing HPV prevalence included higher lifetime number of sex partners and single marital status. After adjustment for potential confounding variables, we found that HPV prevalence increased with higher lifetime number of sexual partners. CONCLUSION These findings, along with those from the companion reports in this issue of the journal, support the sexual route of transmission of the virus.

Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with chronic hepatitis C

Summary.  Assessment of liver fibrosis is important in determining prognosis and evaluating interventions. Due to limitations of accuracy and patient hazard of liver biopsy, non‐invasive methods have been sought to provide information on liver fibrosis, including the European liver fibrosis (ELF) test, shown to have good diagnostic accuracy for the detection of moderate and severe fibrosis. Access to independent cohorts of patients has provided an opportunity to explore if this test could be simplified. This paper reports the simplification of the ELF test and its ability to identity severity of liver fibrosis in external validation studies in patients with chronic hepatitis C (CHC). Paired biopsy and serum samples from 347 naïve patients with CHC in three independent cohorts were analysed. Diagnostic performance characteristics were derived (AUROC, sensitivity and specificity, predictive values), and clinical utility modelling performed to determine the proportion of biopsies that could have been avoided if ELF test was used in this patient group. It was possible to simplify the original ELF test without loss of performance and the new algorithm is reported. The simplified ELF test was able to predict severe fibrosis [pooled AUROC of 0.85 (95% CI 0.81–0.89)] and using clinical utility modelling to predict severe fibrosis (Ishak stages 4–6; METAVIR stages 3 and 4) 81% of biopsies could have been avoided (65% correctly). Issues of spectrum effect in diagnostic test evaluations are discussed. In chronic hepatitis C a simplified ELF test can detect severe liver fibrosis with good accuracy.

Incidence of non‐Hodgkin's lymphoma among individuals with chronic hepatitis B virus infection

Although hepatitis C virus (HCV) infection has been shown to be associated with development of non‐Hodgkins lymphoma (NHL), few studies have investigated the association between chronic HBV infection and NHL. The purpose of this study was to compare the incidence of NHL between patients with and without chronic hepatitis B virus (HBV) infection. Using automated laboratory result and clinical data from two United States health systems, we identified individuals with chronic HBV infection from January 1, 1995 through December 31, 2001. Using each health systems population‐based tumor registry, we identified all cases of NHL diagnosed through December 31, 2002. We excluded any individual with a history of NHL or human immunodeficiency virus (HIV). We fit Cox proportional hazards models to calculate hazard ratios comparing the incidence of NHL between chronic HBV‐infected patients (N = 3,888) and patients without HBV (N = 205,203) drawn from the source populations. We identified 8 NHL cases in the chronic HBV infection cohort and 111 cases in the comparison cohort. Patients with chronic HBV infection were 2.8 times more likely to develop NHL than matched comparison patients (adjusted hazard ratio = 2.80, 95% confidence interval = 1.16‐6.75), after controlling for age, race, sex, income, Charlson comorbidity index, study site, and HCV infection. Conclusion: chronic HBV‐infected patients were nearly 3 times more likely to develop NHL than comparison patients. (HEPATOLOGY 2007.)

Short-term fluctuations in the detection of cervical human papillomavirus DNA

Objective To obtain point and cumulative prevalence estimates of cervical human papillomavirus (HPV) infection using two HPV DNA detection methods with different end point sensitivities; compare cervical swab and cervicovaginal lavage specimen collection methods for subsequent evaluation by polymerase chain reaction (PCR); and evaluate potential effects of the menstrual cycle on HPV DNA detection. Methods Seventy-two college women participated in a 10-week follow-up study. Cervical samples were obtained for HPV DNA detection and typing at each clinic visit, and information was collected concerning menstrual cycle and sexual and hygienic behaviors. Human papillomavirus DNA was detected by the ViraPap HPV DNA dot-blot assay and a broad-spectrum PCR HPV DNA amplification system. Results On a weekly basis, point prevalence for HPV infection by the ViraPap assay ranged from 4.2 to 9.7%, and the cumulative prevalence was 13.9%. Point prevalence by the broad-spectrum PCR assay ranged from 20.8 to 47.2%, and the cumulative HPV prevalence was 58.3%. Using cervicovaginal lavage specimens, we found lower cervical HPV prevalence estimates when compared with cervical swab specimens in the HPV PCR-based assay. No correlation between HPV DNA detection and phase of menstrual cycle was observed. Conclusion Short-term HPV DNA detection is highly variable within individuals; therefore, single-point measurements of cervical HPV have limitations when assessing an individuals HPV status. The relationship between shortterm and long-term HPV DNA persistence profiles may prove relevant to determining the risk of developing cervical intraepithelial neoplasia.

Seroreactivity to Human Papillomavirus Types 16, 18, 31, and 45 Virus-Like Particles in a Case-Control Study of Cervical Squamous Intraepithelial Lesions

Serum IgG antibodies to human papillomavirus (HPV) types 16, 18, 31, and 45 virus-like particles were measured in a nested case-control study of cervical squamous intraepithelial lesions. HPV-16 seroreactivity was strongly associated with HPV-16 DNA detection (odds ratio, 9.0; 95% confidence interval, 4.4-19.4), and similar type specificity was observed for HPV-31 and -45. In contrast, seroreactivity to any type was associated with elevated seroreactivity to all others. Among cases and controls, HPV-16 showed the highest seroprevalence, with 23.8% of 80 cases and 10.5% of 258 controls seroreactive to HPV-16 alone, and another 27.5% and 5.4%, respectively, seroreactive to HPV-16 plus other types. Overall, 24 (30.0%) cases and 17 (6.6%) controls were seroreactive to multiple types. These data suggest that seroreactivity to a given type reflects mainly type-specific HPV infection as measured by DNA detection and may also signal past exposure to other types that are now only serologically detected.