U.S. Center for the Alpha One International Registry

AIR Research

Dan Med Bull 2002 May;49(2):145-58

Epidemiology of emphysema in subjects with severe alpha 1-antitrypsin deficiency.

Seersholm N.

Department of Respiratory Medicine, H:S Bispebjerg Hospital, Copenhangen.

Publication Types:
· Review
· Review, Academic

J Natl Cancer Inst 2001 Jan 17;93(2):121-7

Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries.

Olsen JH, Hahnemann JM, Borresen-Dale AL, Brondum-Nielsen K, Hammarstrom L, Kleinerman R, Kaariainen H, Lonnqvist T, Sankila R, Seersholm N, Tretli S, Yuen J, Boice JD Jr, Tucker M.

Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. jorgen@cancer.dk

BACKGROUND: Epidemiologic studies of the families of patients with ataxia-telangiectasia (A-T), a recessive genetic neurologic disorder caused by mutation of the ATM gene, suggest that heterozygous carriers of an ATM mutation are at increased risk of cancer. A population-based study of cancer incidence in A-T families with unbiased selection and tracing of relatives would confirm this hypothesis. METHODS: We conducted a study in the Nordic countries of 1218 blood relatives of 56 A-T patients from 50 families. The relatives were identified from population registries, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. All statistical tests were two-sided. RESULTS: Among the 56 patients with A-T, we observed six cases of cancer (four leukemias and two non-Hodgkin's lymphomas) compared with 0.16 expected, yielding a standardized incidence ratio (SIR) of 37 (95% confidence interval [CI] = 13 to 80). Among the 1218 relatives, 150 cancers were recorded, with 126 expected (SIR = 1.19; 95% CI = 1.01 to 1.40). Invasive breast cancer occurred in 21 female relatives of A-T patients (SIR = 1.54; 95% CI = 0.95 to 2.36), including five of the 50 mothers (all of whom are obligate ATM mutation carriers) (SIR = 7.1; 95% CI = 2.3 to 17). Relatives who were less likely to be carriers of a mutant ATM allele had no increase or only a modest, statistically nonsignificant increase in the risk of breast cancer. There was no evidence of increased risk for cancer at any other site. CONCLUSIONS: We confirmed the previously recognized high risk of lymphoma and leukemia in A-T patients. Our data are also consistent with an increased risk of breast cancer among blood relatives of A-T patients. The epidemiologic findings suggest, however, that, even if ATM mutations are responsible for some breast cancer cases, ATM is a relatively weak genetic risk factor for the disease.

J R Soc Health 1999 Jun;119(2):92-6

Self-reported smoking habits, biochemical markers, and nicotine dependence in a sample of the Danish population.

Seersholm N, Nielsen NH, Tonnesen P.

Bispebjerg Hospital, Pulmonary Department P, Copenhagen, Denmark.

This study reports the smoking habits in a Danish population, evaluates plasma cotinine and thiocyanate levels in the detection of 'slips' (subjects participating in smoking cessation trials who begin to smoke a few cigarettes per week) and provides distribution scores on questionnaire measures of nicotine dependence. A total of 599 subjects with a mean age of 41 years participated in the study. Of these 46% were current smokers with no difference in the proportion of males(46%) and females(45%) and with a mean cigarette consumption of 12.7 daily. Plasma samples were analyzed for cotinine and thiocyanate, and the smokers completed two questionnaires to measure nicotine dependence: the Fagerstrom Tolerance Questionnaire and the modified Horn-Russell scale. The mean plasma cotinine was 207 micrograms/l for smokers, 14.4 micrograms/l for occasional smokers and 8.0 micrograms/l for non-smokers (ex-smokers and never-smokers). For plasma thiocyanate the levels were 130 mg/l, 54.8 mg/l, and 54.3 mg/l, respectively. The mean Horn-Russell score was 7.4 and the mean Fagerstrom score was 5.9. The two tests correlated with a t-value of 0.61 (p < 0.001) and the scores in both tests increased with increasing cigarette consumption. In conclusion, 75% of the smokers consumed 10 or more cigarettes per day and males smoked more cigarettes than females. It was impossible to distinguish occasional smokers (slips) from non-smokers using plasma cotinine or thiocyanate levels. We suggest that studies are needed to evaluate if light smokers benefit from nicotine replacement therapy because they achieve plasma cotinine levels which are similar to those seen when using patches for nicotine replacement therapy.

Br J Cancer 1999 Feb;79(3-4):673-9

Cancer risk in close relatives of women with early-onset breast cancer--a population-based incidence study.

Olsen JH, Seersholm N, Boice JD Jr, Kruger Kjaer S, Fraumeni JF Jr.

Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen.

Inherited susceptibility to breast cancer is associated with an early onset and bilateral disease. The extent of familial risks has not, however, been fully assessed in population-based incidence studies. The purpose of the study was to quantify the risks for cancers of the breast, ovary and other sites of close relatives of women in whom breast cancer was diagnosed at an early age. Records collected between 1943 and 1990 at the Danish Cancer Registry were searched, and 2860 women were found in whom breast cancer was diagnosed before age 40. Population registers and parish records were used to identify 14 973 parents, siblings and offspring of these women. Cancer occurrence through to 31 December 1993 was determined within the Cancer Registry's files and compared with national incidence rates. Women with early-onset breast cancer were at a nearly fourfold increased risk of developing a new cancer later in life (268 observed vs. 68.9 expected). The excess risk was most evident for second cancer of the breast (181 vs. 24.5) and for ovarian cancer (20 vs. 3.3). For mothers and sisters, risks for cancers of the breast and ovary were significantly increased by two- to threefold. Bilateral breast cancer and breast-ovarian cancer were very strong predictors of familial risks, with one in four female relatives predicted to develop breast and/or ovarian cancer by age 75. Mothers had a slightly increased risk of colon cancer, but not endometrial cancer. The risk for breast cancer was also increased among fathers (standardized incidence ratio 2.5; 95% CI 0.5-7.4) and especially brothers (29; 7.7-74), although based on small numbers. The risk for prostatic cancer was unremarkable. In this large population-based survey, the first-degree relatives of women who developed breast cancer before age 40 were prone to ovarian cancer as well as male and female breast cancer, but not other tumours that may share susceptibility genes with breast cancer.

Am J Gastroenterol 1999 Jan;94(1):86-91

Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study.

Bytzer P, Christensen PB, Damkier P, Vinding K, Seersholm N.

The Department of Medical Gastroenterology S, Odense University Hospital, and Danish Cancer Society, Copenhagen.

OBJECTIVE: We described incidence rates of esophageal adenocarcinoma in Denmark in a 20-yr period and determined the proportion of patients diagnosed with esophageal adenocarcinoma who had a previous diagnosis of Barrett's esophagus, making them potential candidates for endoscopic surveillance. METHODS: Rates of esophageal and gastric cancers were collected from the Danish Cancer registry for the period 1970-1991. The registry was used to identify all cases of esophageal adenocarcinoma in the period 1987-1992. Medical records were retrieved and details concerning previous diagnosis of reflux disease and Barrett's esophagus were recorded. RESULTS: The age- and gender-adjusted incidence of esophageal adenocarcinoma increased eightfold, from 0.3/10(5)/yr in 1970 to 2.3/10(5)/yr in 1990. This increase could not be explained by changes in classification or diagnostic routines. Medical data were retrieved for 524 of the 578 cases of esophageal adenocarcinoma reported during the period 1987-1992. A history of reflux symptoms or a diagnosis compatible with reflux was reported in 113 of 524 patients. A total of 119 patients (23%) had previously been investigated for dyspepsia or reflux symptoms, most often by endoscopy. A previous diagnosis of Barrett's esophagus was found in only 1.3% of the cancer patients. CONCLUSIONS: The rate of esophageal adenocarcinoma in Denmark has increased eightfold over a 20-yr period, and this increase is not explained by changes in classification or diagnostic routines. More than 98% of esophageal adenocarcinomas were found in patients who could not have entered endoscopic surveillance, as Barrett's esophagus had not been diagnosed before the cancer diagnosis. Endoscopic surveillance to detect dysplasia may be an option for the individual patient with Barrett's esophagus, but these screening programs are not likely to reduce the death rate from esophageal adenocarcinomas in the general population.

Thorax 1998 Dec;53(12):1096

Clinical features and prognosis of life time non-smokers with severe alpha 1-antitrypsin deficiency.

Seersholm N, Kok-Jensen A.

Respiratory Clinic, Rigshospitalet, Copenhagen, Denmark.

BACKGROUND: The hereditary disorder alpha 1-antitrypsin deficiency is characterised by development of severe emphysema at an early age with smoking being the most significant additional risk factor. The purpose of the present paper was to analyse potential risk factors other than smoking for emphysema and to estimate the prognosis of life time non-smokers. METHODS: Patients were identified through the files of the Danish alpha 1-antitrypsin deficiency register which contains information on more than 700 persons with the condition. Many of the patients, the non-index cases, were identified from family studies. RESULTS: There were 75 life time non-smokers with PiZ (27 index cases and 48 non-index cases) aged 20 years or more at entry. Twenty one subjects died during the follow up period. The Standardised Mortality Ratio (SMR) was 3.0 (95% confidence intervals (CI) 1.9 to 4.6). There was no significant difference in SMR between males and females. The SMR was 8.8 (95% CI 5.0 to 14) for the index cases and 0.96 (95% CI 0.3 to 2.3) for the non-index cases based on five deaths. The overall mean % predicted forced expiratory volume in one second (FEV1) at entry was 83% with a significant difference between index cases (54%) and non-index cases (100%) (p < 0.001). The difference in the ratio of FEV1 to forced vital capacity (FVC) was also highly significant with values of 0.57 and 0.79 for index and non-index cases, respectively (p < 0.001). In the non-index group only three had an FEV1% predicted of less than 70%. CONCLUSIONS: Occupational exposure to airway irritants did not have any significant influence on the development of emphysema. Only a few life time non-smokers develop severe emphysema; most never develop pulmonary symptoms and thus remain undetected unless family members of index cases are screened.

Respir Med 1998 Feb;92(2):241-5

Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema?

Seersholm N, Kok-Jensen A.

Bispebjerg Hospital, Department of Respiratory Medicine, Copenhagen, Denmark.

It is well documented that the severe hereditary disorder alpha 1-antitrypsin deficiency (alpha 1ATD) PiZZ is a strong risk factor for emphysema, especially among smokers, but the role of intermediate alpha 1ATD PiMZ and PiSZ in the development of emphysema remains uncertain. In this study, we have evaluated mortality and lung function of 94 persons with intermediate alpha 1ATD PiSZ of whom 66 were non-index cases, i.e. persons ascertained through family studies. The index cases and the non-index cases were similar with respect to sex, age and follow-up time, but differed in smoking habits and FEV1. Among the smokers there was no significant difference in pack-years between index cases and non-index cases. The overall Standardized Mortality Ratio (SMR) was 1.6 (95% confidence intervals (CI): 0.8-2.7). For the index cases the SMR was 4.3 (95% CI: 1.9-8.5) and for the non-index cases it was 0.8 (95% CI: 0.3-1.8). In the index group six patients died of pulmonary emphysema, one of pulmonary fibrosis, and one of colon cancer. In the non-index group two died of pulmonary emphysema, two of pneumonia, and one of cerebral haemorrhage. The mean initial FEV1% predicted among the index cases was 59% compared with 94% among the non-index cases. Based on the analysis of the non-index cases it is concluded that only a small fraction of persons with the PiSZ phenotype are at increased risk of developing pulmonary emphysema, and at an older age than persons with the PiZ phenotype.

Eur J Cancer 1997 Dec;33(14):2376-9

Cancer in the offspring of parents with lung cancer.

Seersholm N, Hertz H, Olsen JH.

Division for Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.

Despite several studies on the role of passive smoking in the development of childhood cancer, particularly leukaemia, lymphomas and brain cancer, no definitive answer has yet been provided. The aim of the cohort study reported here was to analyse the incidence of cancer in the offspring of young lung cancer patients on the basis of the assumption that all of the offspring were exposed passively to smoke. The files of the Danish Cancer Registry provided 3348 cases of lung cancer patients born after 1935, and their offspring (n = 6417) were identified through the Danish Population Register. The files of the offspring were then linked with the files of the Danish Cancer Registry and the numbers of cancers observed in the offspring were compared with those expected from national age-specific and calendar-time-specific rates. A total of 135,333 person-years was the basis for analysis. Twenty-six cancers were observed, with 30.3 expected, yielding a standardised incidence ratio (SIR) of 0.9 (90% confidence interval (CI), 0.6-1.2). There was no excess of brain tumours, leukaemias or lymphomas. Stratification for sex of the lung cancer patients revealed a non-significantly increased risk for both non-Hodgkin's lymphoma (three cases; SIR = 3.4; 90% CI: 0.9-8.7) and Hodgkin's disease (three cases; SIR = 2.6; 90% CI: 0.7-6.6) in the offspring of female lung cancer patients. These results suggest that there is little evidence of an excess cancer risk in childhood, whether due to passive smoking or to as yet unidentified genetic factors, among the offspring of people who develop lung cancer. However, the results are limited by the fact that exposure was only assessed indirectly, with no measurement of actual cigarette consumption made.

Respir Med 1997 Feb;91(2):77-82

Body mass index and mortality in patients with severe alpha 1-antitrypsin deficiency.

Seersholm N.

Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark.

It appears that patients with advanced stages of chronic obstructive pulmonary disease, and particularly emphysema, lose weight and have higher mortality even after controlling for lung function. In the present study, mortality of alpha 1-antitrypsin-deficiency patients PiZ as a function of body mass index (BMI) with control for FEV1, sex and smoking habits was studied. A total of 342 patients participated with a mean follow-up time of 7.6 yr. Ninety patients had BMI under 20 kg m-2, which was the cut-off defining underweight patients. The patients were divided into three groups according to their initial FEV1 % predicted: < 30%, 30-64% and > or = 65%. The underweight patients had significantly higher mortality in the two groups with the lowest FEV1 % predicted. A Cox regression model was applied to control for potential confounders. The risk ratio for the underweight patients was 1.6 (P = 0.03) after controlling for FEV1, age, sex and smoking habits. It is concluded that low body weight is an independent predictor of mortality, but the reason is still unclear.

Ugeskr Laeger 1997 Jan 13;159(3):288-93

[Cancer in the parents of children with cancer]

[Article in Danish]

Olsen JH, Boice JD, Seersholm NJ, Bautz A, Fraumeni JF.

Kraeftens Bekaempelse, Kobenhavn.

Certain types of cancer in children and young adults have been linked with an increased risk of cancer in close relatives. However, the relation between childhood cancer and familial risk remains to be fully assessed in population-based studies. We conducted a nationwide study in Denmark of 11,380 parents of children with cancer. The children were identified from records in the Danish Cancer Registry; their parents were identified from population registers. The occurrence and rate of cancer in the parents were determined with use of the Cancer Registry's files and compared with national incidence rates for various categories of tumour. Overall, 1445 cancers were diagnosed in the parents, as compared with 1496 expected from national incidence rates, to yield standardized incidence ratios of 0.97 (95 percent confidence interval, 0.92 to 1.02) for all parents, 0.99 for mothers, and 0.94 for fathers. The lower rate of cancer among fathers reflected their lower standardized incidence ratio for lung cancer (0.76; 95 percent confidence interval, 0.63 to 0.91), as calculated from 114 observations. Genetic determinants are important in several types of childhood cancer, but the genetic susceptibility to tumours does not generally extend to the parents of children with cancer, not do the patterns of incidence point to the influence of shared environmental factors. Thus, cancer in children should not be viewed as a general marker for an increased risk of cancer in the patient's parents.

N Engl J Med 1995 Dec 14;333(24):1594-9

Cancer in the parents of children with cancer.

Olsen JH, Boice JD Jr, Seersholm N, Bautz A, Fraumeni JF Jr.

Division for Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.

BACKGROUND. Certain types of cancer in children and young adults have been linked with an increased risk of cancer in close relatives. However, the relation between childhood cancer and familial risk remains to be fully assessed in population-based studies. METHODS. We conducted a nationwide study in Denmark of 11,380 parents of children with cancer. The children were identified from records in the Danish Cancer Registry; their parents were identified from population registers. The occurrence and rate of cancer in the parents were determined with use of the Cancer Registry's files and compared with national incidence rates for various categories of tumor. RESULTS. Overall, 1445 cancers were diagnosed in the parents, as compared with 1496 expected from national incidence rates, to yield standardized incidence ratios of 1.0 (95 percent confidence interval, 0.9 to 1.0) for all parents, 1.0 for mothers, and 0.9 for fathers. The lower rate of cancer among fathers reflected their lower standardized incidence ratio for lung cancer (0.8; 95 percent confidence interval, 0.6 to 0.9), as calculated from 144 observations. CONCLUSIONS. Genetic determinants are important in several types of childhood cancer, but the genetic susceptibility to tumors does not generally extend to the parents of children with cancer, nor do the patterns of incidence point to the influence of shared environmental factors. Thus, cancer in children should not be viewed as a general marker for an increased risk of cancer in the patients' parents.

Am J Respir Crit Care Med 1995 Dec;152(6 Pt 1):1922-5

Decline in FEV1 among patients with severe hereditary alpha 1-antitrypsin deficiency type PiZ.

Seersholm N, Kok-Jensen A, Dirksen A.

Pulmonary Department P, Bispebjerg Hospital, Copenhagen, Denmark.

Severe alpha 1-antitrypsin (alpha 1-AT) deficiency is characterized by a decrease in serum alpha 1-AT to values < 20% of normal. Severe airflow obstruction, most commonly due to pulmonary emphysema secondary to the destruction of pulmonary elastic tissue, may develop at an early age in persons with alpha 1-AT deficiency. The purpose of this study was to estimate the annual decline in FEV1 (delta FEV1) in alpha 1-AT-deficient patients, to compare delta FEV1 in a referral population (index cases) with subjects found through family studies (nonindex cases), and to evaluate the role of smoking cessation on delta FEV1. One hundred and sixty-one subjects from the Danish alpha 1-AT-deficiency study who were older than 25 yr and who had a recorded smoking history and at least two spirometric examinations 1 yr apart were studied. The delta FEV1 for each individual was determined by regression analysis of FEV1 on follow-up time. The overall mean delta FEV1 was 81 ml/yr. There was no significant difference in delta FEV1 between 113 index cases and 48 nonindex cases even after controlling for age, initial FEV1, sex, and lifetime tobacco consumption. One hundred of the subjects were ex-smokers, 18 had never smoked, and 43 were current smokers. The mean delta FEV1 among the current smokers was 132 ml/yr, versus 52 ml/yr among the ex-smokers (p < 0.001). For the never-smokers, the mean delta FEV1 was 86 ml/yr.

Ugeskr Laeger 1995 Apr 24;157(17):2432-5

[Survival of patients with severe alpha 1-antitrypsin deficiency]

[Article in Danish]

Seersholm NJ, Kok-Jensen A, Dirksen A.

Lungemedicinsk afdeling P, Bispebjerg Hospital, Kobenhavn.

Previous estimates of survival of patients with alpha-1-antitrypsin deficiency (alpha 1ATD) have been based on selected patients. In this paper we have compared the survival of 397 patients with severe alpha-1-antitrypsin deficiency either ascertained because of pulmonary impairment (index cases) or ascertained through family studies (non-index cases). The patients were drawn from the nationwide Danish alpha 1ATD register. The overall median survival was 54.5 years with no significant difference between males and females. Survival for index cases was less than for the non-index cases regardless of smoking history (49.4 years and 69.3 years respectively). When we analyzed index cases and non-index cases separately there was no difference between the survival of smokers and never-smokers in the index group. In the non-index group smokers had a shorter survival than never-smokers. The survival of non-index never-smokers was similar to the survival of the normal Danish population. We conclude that the prognosis of severe alpha 1ATD is better than previously assumed, and that although smoking is a major risk factor the development of emphysema in patients with severe alpha 1ATD is multifactorial.

Ugeskr Laeger 1995 Apr 10;157(15):2134-8

[Ataxia telangiectasia]

[Article in Danish]

Hansen LK, Wulff K, Seersholm NJ.

Odense Universitetshospital, borneafdelingen.

Ataxia telangiectasia is a genetically determined multi-system disorder in which senile skin changes are at an early stage. The patients have progressive neurological disability, cellular and humoral immunodeficiencies and increased cancer incidence. Heterozygous carriers of the gene, estimated to comprise about 1% of the general population, have an increased risk of cancer. We have initiated an identification of a cohort of patients and their relatives in order to evaluate their cancer risk.