Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study.

The benefits of screening hepatitis B surface antigen (HBsAg)-positive carriers for hepatocellular carcinoma (HCC) in terms of long-term survival have not been established. We conducted a prospective 16-year, population-based cohort study to determine the impact of screening for HCC in 1,487 HBsAg-positive Alaska native carriers with alpha-fetoprotein (AFP) determinations every 6 months. Men and nonpregnant women with an elevated AFP level were evaluated for the presence of HCC by ultrasound (US) examination. The long-term survival rate for patients whose HCC was detected by the screening program was compared with a historical control group of Alaska native patients with HCC from the same population who were clinically diagnosed with HCC between 1969 and October 1982, through a National Cancer Institute-sponsored Cancer Registry. Between October 1982 and December 1998, 26,752 AFP determinations in HBsAg carriers were performed. One or more AFP elevations were found in 61 men and 39 nonpregnant women. HCC was diagnosed in 32 patients (24 men and 8 women). HCC tumors less than 6 cm were found in 23 patients; 22 patients had resections, and 1 patient refused a resection. Compared with 12 patients with hepatitis B virus (HBV)-related HCC diagnosed from 1969 to October 1982, before this program, the 5- and 10-year survival rate for the 32 patients with HCC were 42% (P =.008) and 30% (P =.07), respectively. Five- and 10-year tumor-free survival rates for carriers who had a normal AFP level on initial screening and subsequently developed HCC were 29% (P =.004) and 24% (P =.024), respectively. Screening of HBsAg carriers with semiannual AFP was effective in detecting most HCC tumors at a resectable stage and significantly prolonged survival rates when compared with historical controls in this population.

Hepatocellular carcinoma not related to hepatitis B virus infection among Alaska natives.

Chronic infection with hepatitis B or C viruses is a common underlying condition in patients with hepatocellular carcinoma worldwide. We studied serum and liver tissue from a cohort of Alaska natives with hepatocellular carcinoma (HCC) for evidence of hepatitis B, C and G viral infection using conventional serological tests as well as the sensitive polymerase chain reaction. Evidence of HBV infection was found in 25 and possible HCV infection in two cases. Among the remaining 11 patients, four had a history of recent or remote alcoholism while seven had no recognizable risk factors for HCC. Only one was seropositive for HGV RNA and that was an individual with a history of alcoholism. Non-tumorous liver tissue was available for study in six of these seven cases. Histological features of chronic hepatitis were present in five. Thus, at least five of 38 (13%) Alaska natives with HCC appeared to have chronic hepatitis not related to HBV or HCV infection, suggesting the possibility of some form of previously unrecognized chronic liver disease predisposing to HCC.

Risk factors for cervical intraepithelial neoplasm in Alaska Native women: a pilot study.

Although rates for invasive cervical cancer have declined over the past twenty years among Alaska Native women, they continue to show high rates of pre-invasive cervical lesions (cervical intraepithelial neoplasia, or CIN). We investigated risk factors for CIN II/III among Alaska Native women in a pilot case-control study. Cases (n = 26) included women with biopsy-proven CIN II/III, while controls (n = 52) had normal cervical epithelium. The strongest risks associated with CIN II/III were HPV infection of any type (Crude Odds Ratio [OR] 8.4, 95% Confidence Interval [CI]: 2.9-29.4), HPV 16 infection (OR 40.8, 95% CI: 9.4-176.4), and a family history of cervical dysplasia (OR 3.9, 95% CI: 1.3-11.3). We also found that use of depot-medroxy progesterone acetate was associated with CIN (OR 3.0, 95% CI: 1.1-8.5). A larger investigation would be necessary to allow adequate evaluation of these, and other, risk factors for CIN among Alaska Native women.

Alaska Native cancer update: incidence rates 1989-1993.

Five-year average annual age-adjusted cancer incidence rates for Alaska Natives (Eskimos, Indians, and Aleuts) for the most recent period (1989-1993) are compared to rates of 20 years earlier. Rates for all cancers combined increased 28 and 25% in men and women, respectively, during the 25-year interval. Increases were seen in men in cancers of the lung, prostate, and colon and in women for cancers of the lung, breast, and corpus uteri. Rates are also compared to data from the the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for United States whites. Rates for all cancers combined in Alaska Native women are now similar to those of United States whites, whereas rates in Alaska Native men are lower than the United States, but only 10% lower. Significant site-specific differences previously reported between Alaska Natives and United States whites persist.

p53 is not mutated in hepatocellular carcinomas from Alaska Natives.

Hepatocellular carcinoma is common among Alaska Natives. The known risk factor in this population is hepatitis B viral infection; fungal toxins, including aflatoxin B1, have not been detected in foodstuffs. In this series of 14 patients (including 4 siblings and 2 second cousins), 3 patients were less than 12 years old at diagnosis of hepatocellular carcinoma, 8 patients were 13-24 years old, and 3 patients were more than 60 years old. Since p53 mutations occur in 29% of hepatocellular carcinomas worldwide, we tested the tumors for p53 mutations and serum samples for anti-p53 antibodies. Serum samples from these 14 patients did not contain detectable levels of anti-p53 antibodies. Loss of heterozygosity within the p53 locus was not detected in any of 9 informative cases. Immunohistochemical analysis for p53 protein accumulation was negative in all of 11 tumors. DNA sequence analysis of 12 tumor samples showed no evidence of p53 mutation in the highly conserved regions included in exons 5-8. These data, combined with one case from a previous report, indicate a mutation frequency of 0 of 13, which differs significantly from the worldwide frequency of 29% (chi 2 3.9; P = 0.048). These results indicate that liver carcinogenesis among Alaska Natives occurs independently of a traditional p53 pathway. The familial clustering and early onset in this population strongly suggest an inherited genetic predisposition to develop liver cancer. Germline mutations in a tumor suppressor or a cancer susceptibility gene are likely. Future studies of these samples should include investigations of candidate suppressor or susceptibility genes which map to chromosomal regions commonly deleted in liver cancers.

Rheumatoid arthritis in Tlingit Indians: clinical characterization and HLA associations.

OBJECTIVE: To characterize the features of rheumatoid arthritis (RA) in Tlingit Indians, to identify the HLA-DR alleles associated with RA in the Tlingit, and to determine whether disease severity or specific clinical manifestations correlate with the presence of specific HLA antigens. METHOD: Thirty-seven Tlingit patients with RA and 75 controls were evaluated clinically; comparative HLA studies were carried out in 33 patients and 62 controls. RESULTS: The results of this clinical study of RA in the Tlingit confirms that the disease found in them is classical RA, characterized by an early age of onset, a high frequency of nodules, serum rheumatoid factor (RF) and antinuclear antibodies (ANA); an often severe clinical course, with a high frequency of erosive disease and frequent need for surgical joint repair, and an often positive family history. In Tlingit volunteers who did not have RA we also found an increased prevalence of RF and ANA. Neither HLA-DR1 nor DR4 was found to be associated with RA in the Tlingit. The commonest DR antigen in patients with RA was DR14. The most frequent DRB1 allele was DRB1*1402 (Dw16). CONCLUSION: The Tlingit population had a very high frequency of the DRB1*1402 allele, which shares key sequence homology with DRB1*0401 (Dw4) and DRB1*0101 (Dw1), associated with RA in other racial groups. No correlations were found between specific HLA-DRB1 alleles or combinations of alleles and specific disease features or severity.

Protection provided by hepatitis B vaccine in a Yupik Eskimo population. Seven-year results.

The long-term immunogenicity and protection provided by a plasma-derived hepatitis B vaccine (Heptavax B) was determined in a cohort of susceptible persons immunized in 1981. In this study 1581 susceptible persons were immunized with the recommended three-dose regimen of hepatitis B vaccine. After 7 years, 74% of vaccinees retained antibody to hepatitis B surface antigen (anti-HBs) levels of 10 mIU/mL or more. Anti-HBs levels at 7 years varied inversely with age and directly with the level of anti-HBs attained 1 year after the first dose. During the 7 years after the first dose of vaccine, five vaccine responders and three other persons developed antibody to hepatitis B core antigen and their level of anti-HBs increased. None developed detectable hepatitis B surface antigen or clinical hepatitis. This update of an ongoing study continues to suggest that the risk of hepatitis B virus infection to most persons with an initial anti-HBs response to hepatitis B virus vaccine of 10 mIU/mL or greater is low, regardless of the initial antibody level.

Clustering of hepatocellular carcinoma in Alaska Native families.

Alaska Natives have a high incidence of hepatocellular carcinoma (HCC), with regional, ethnic, village, and familial clustering. During 1969-1988, 15 of the 45 incident cases of HCC in Alaska Natives occurred in 5 families. This report presents epidemiologic, virologic, and immunogenetic data on these 5 families. The results of hepatitis B virus (HBV) serologic testing indicates that HBV infection was an important factor in 4 of the 5 families. Human lymphocyte antigen (HLA) testing was performed in 3 families. The HLA results are reviewed in relationship to the familial clustering of HCC.

Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population.

In 1981, a hepatitis B virus vaccine demonstration project was conducted in 1630 Yupik Eskimos in southwest Alaska. Levels of antibody to hepatitis B surface antigen and markers for hepatitis B virus infection in vaccinees were monitored yearly for 5 years. After 5 years of follow-up, 19% of those who initially had an immune response to vaccine of 10 sample ratio units or greater subsequently had levels of antibody to hepatitis B surface antigen lower than 10 sample ratio units. During the 5 years after the first dose of vaccine, in three responders and one person with an antibody to hepatitis B surface antigen response lower than 10 sample ratio units, antibody to hepatitis B core antigen developed, and the level of antibody to hepatitis B surface antigen was boosted. Hepatitis B surface antigen did not develop in any subjects, and none had clinical hepatitis. In the 5 years following the demonstration project, the annual incidence of hepatitis B virus infection decreased from 50 cases per 1000 population before the vaccine trial to 0.45 per 1000.

Increased risk of cancer in siblings of Alaskan native patients with nasopharyngeal carcinoma.

Alaskan Natives (Eskimos, Indians, Aleuts) are at increased risk of developing nasopharyngeal cancer (NPC) and there is family clustering of NPC. This study reviewed the total cancer experience of relatives of NPC patients and found that siblings of Eskimo NPC patients had a nearly threefold risk. No cancer family syndrome was identified and the cancers diagnosed in the siblings were similar to those seen in the general Alaskan Eskimo population.

Food-borne botulism in Alaska, 1947-1985: epidemiology and clinical findings.

We reviewed records of all food-borne outbreaks of botulism in Alaska from 1947 through 1985. Fifty-nine confirmed or suspected outbreaks with 156 cases were reported. All outbreaks occurred in Alaska Natives and were associated with eating traditional Alaska Native foods. Forty-four (75%) of the outbreaks were laboratory confirmed and involved 133 persons. The overall annual incidence of confirmed or suspected botulism was 8.6 cases per 100,000 population. Seventeen persons died, an overall case-fatality rate of 11%. Type E toxin accounted for 32 (73%) laboratory-confirmed outbreaks; type A, six (14%); and type B, five (11%). Forty-one cases demonstrated botulinal toxin in one or more specimens (serum, gastric contents, or stool). Of the 41 botulinal toxin-positive persons, 38 (93%) had at least three of the commonly recognized pentad of signs or symptoms--nausea and vomiting, dysphagia, diplopia, dilated and fixed pupils, or dry mouth and throat--and 20 (49%) required respiratory assistance.

Delayed development of antibody to hepatitis B surface antigen after symptomatic infection with hepatitis B virus.

During a 2-year period, 38 patients with clinical hepatitis B virus infection were seen at the Public Health Service Alaska Native Hospital in Bethel. This hospital serves an area in southwest Alaska that is hyperendemic for hepatitis B virus. The patients came to the hospital at various times from 15 scattered villages, and 92% were Eskimo. None of the patients had a recent history of hypodermic injection or blood transfusions. Twenty-five patients, all originally positive for hepatitis B surface antigen (HBsAg), were followed for up to 5 years after onset of illness, and 15 were either slow to develop, or never developed, antibody to HBsAg (anti-HBs), although only one patient became a chronic carrier of HBsAg. Six patients had a prolonged "window phase" between the disappearance of HBsAg and the appearance of anti-HBs which lasted for more than 1 year. Three patients had only transient anti-HBs after HBsAg disappeared, and five never developed measurable anti-HBs at all. All patients had antibody to hepatitis B core when both HBsAg and anti-HBs were absent. In contrast to studies in other populations, only 42% had anti-HBs 1 year after onset of illness, 63% had it at 18 months, 70% had it at 2 years, and 80% had it at 5 years. Factors related to ethnicity might account for the differences in the development of anti-HBs after acute symptomatic hepatitis B virus infection seen in Eskimos when compared with whites.

Acute glomerulonephritis and streptococcal skin lesions in Eskimo children.

Poststreptococcal acute glomerulonephritis often follows impetigo and can occur in epidemics. From 1975 through 1977, an epidemic of poststreptococcal acute glomerulonephritis occurred in Alaska. Fifty children required hospitalization, while 25 less seriously ill children were treated as outpatients. Sixty-seven percent of these 75 children had direct evidence of recent skin infections. Serotypes 49-14 and NT-14 were the most common streptococcal isolates. In villages in the epidemic area, approximately 15% of children had impetigo and more than 60% of lesions cultured were positive for group A streptococci. Impetigo rates in the epidemic area were similar to those found in nonepidemic areas. However, the introduction of the nephritogenic streptococcal serotypes not recently present in this population apparently led to the development of the epidemic.