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Aim: To describe the incidence, clinical presentation and paraclinical findings in childhood sarcoidosis in Denmark, 1979-1994. Methods: Patients ( n = 5536) with a diagnosis of sarcoidosis were drawn from the nationwide Patient Registry; 81 patients were ≤15 y of age. The diagnosis of sarcoidosis was reconfirmed in 48/81 (59%) patients. In 35/48 (73%) patients, diagnosis was verified by histology, and in 13 it was substantiated by paraclinical/clinical findings. Results: The series comprised 26 boys and 22 girls (male/female ratio 1.18). Median age at diagnosis was 13 y (range 0.7-15). In 1979-1994 the incidence was 0.29 per 100 000 person-years ≤15 y of age. The incidence was 0.06 in children ≤4 y of age and increased gradually with age to 1.02 in children aged 14-15 y. General malaise, fever, weight loss, abdominal discomfort, respiratory symptoms, lymphadenopathy and central nervous system symptoms were common; 31% of patients had erythema nodosum, 12.5% sarcoid skin lesions, 25% uveitis/iridocyclitis and 4.2% sarcoid arthritis. Chest X-rays were normal (stage 0) in 10% of patients, and showed pulmonary infiltrates stage I in 71%, stage II in 8.3% and stage III in 8.3%. Lung function tests were examined in 13 patients: 50% had decreased FEV 1 and vital capacity, 80% decreased D L CO. Haemoglobin values were normal. Some patients had mild leukopenia, some moderate leukocytosis and a few had moderate eosinophilia. Erythrocyte sedimentation rate was elevated in 40% of the patients. Plasma calcium was elevated in 30% of the patients; 4 patients had severe hypercalcaemia and elevated plasma creatinine, and 1 patient had nephrocalcinosis. Serum angiotensin-converting enzyme was elevated in 55% of the patients. Liver function tests were normal with no sarcoid hepatitis. Urinary examination (glucose, albumin, haemoglobin) was normal in 96% of the patients; the patient with nephrocalcinosis had albuminuria and haematuria. Conclusion: The incidence of sarcoidosis in Danish children is low and increases with age. Sarcoidosis in young children may present clinical features that are different from the appearance of those in older children and often constitute a diagnostic challenge. In older children, the clinical appearance has many features in common with the presentation in adults. [ABSTRACT FROM AUTHOR]

Analysis of the common C282Y and H63D mutations in the HFE gene is widely used to diagnose hereditary hemochromatosis (HH). The aim of this study was to evaluate the efficiency with which different hospitals and general practitioners select patients for HH genotype and to determine the distribution of HFE mutations in such patients. Nine hundred unrelated patients from Danish hospitals and general practitioners (group A) and 69 consecutive patients from a specialized liver unit (group B) were examined for HFE substitutions using multiplex real-time polymerase chain reaction. In group A we found 13.0% (0%) C282Y homozygotes, 5.8% (2.6%) H63D/C282Y compound heterozygotes and 1.9% (3.1%) S65C heterozygotes. The values for 420 Danish blood donors are shown in parentheses. The distribution of genotypes in group B was similar to that of the blood donors. Serum ferritin, transferrin iron saturation and pathological data were collected from 38 randomly selected C282Y homozygotes, 36 H63D/C282Y compound heterozygotes, 19 H63D heterozygotes, 17 S65C heterozygotes and 144 wild-types. All of the C282Y homozygotes and 28% of the compound heterozygotes were diagnosed as HH patients. There was no evidence of HH in the H63D homozygotes or S65C heterozygotes. Moreover, 7 wild-type patients, 2 C282Y heterozygote patients and one H63D heterozygote patient fulfilled the criteria for HH. The significant enrichment of HH among associated genotype samples submitted for HFE testing indicates that the clinical selection is generally adequate. However, the study showed substantial deviation in the selection efficiency among the various hospitals and general practitioners. [ABSTRACT FROM AUTHOR]

Presents a long term study on the association between food intake and serum ferritin in Denmark. Design of the study; Number of persons in the sample; Contention that dietary items were poor indicators of serum ferritin; Use of the information on alcohol intake and blood loss for iron status.

Iron status was assessed by measuring serum (S-) ferritin and hemoglobin (Hb) in a population survey comprising 1359 nonpregnant Danish women, in age cohorts of 30, 40, 50, and 60 years; 809 were premenopausal and 550 postmenopausal. Median age for menarche was 14 years, for menopause (artificial and natural) 48 years. Premenopausal women had lower S-ferritin (median 37 micrograms/l) than postmenopausal women (median 71 micrograms/l; p less than 0.0001). Of the premenopausal women, 17.7% had S-ferritin less than 15 micrograms/l (i.e., depleted iron stores), and 23.1% S-ferritin of 15-30 micrograms/l (i.e., small iron stores). Corresponding figures in postmenopausal women were 3.3% and 10.3%. Hb values in premenopausal women were mean 137 +/- 10 (SD) g/l (8.5 +/- 0.6 mmol/l) vs. 140 +/- 10 g/l (8.7 +/- 0.6 mmol/l) in postmenopausal women (p less than 0.0001); 4.1% of pre- and 3.3% of postmenopausal women had values less than 121 g/l (7.5 mmol/l). Iron deficiency anemia (i.e., S-ferritin less than 15 micrograms/l and Hb less than 121 g/l) was found in 2.6% of pre- and 0.36% of postmenopausal women. Premenopausal multipara had lower S-ferritin than nulli- and unipara (p less than 0.04). The use of oral contraceptives had a marked influence on iron stores; premenopausal women taking the pill had higher S-ferritin and a lower frequency of depleted iron reserves than nonusers (p less than 0.01). Postmenopausal estrogen treatment had no influence on S-ferritin or Hb. [ABSTRACT FROM AUTHOR]

The general impact of blood donation on iron status was studied in a population survey comprising 1359 nonpregnant Danish women in age cohorts of 30, 40, 50, and 60 years; 809 were premenopausal and 550 postmenopausal; 180 (13%) were blood donors. Iron stores were assessed by serum (S)-ferritin and hemoglobin (Hb). Hb levels were not significantly different in donors: mean 137 +/- 10 (SD) g/l (8.5 +/- 0.6 mmol/l) compared with nondonors, 139 +/- 11 g/l (8.6 +/- 0.7 mmol/l). Values less than 121 g/l (7.5 mmol/l) were observed in 3.3% of donors vs 3.8% of nondonors. Correlations between S-ferritin and Hb were without practical relevance: rs = 0.29, p less than 0.0001 in donors vs rs = 0.22, p less than 0.0001 in nondonors. Blood donation had a profound influence on iron status, especially in the premenopausal women population. Donors had lower S-ferritin than nondonors in all age-groups and in pre- and postmenopausal groups (p less than 0.001 in all groups). Premenopausal donors had a median S-ferritin of 31 micrograms/l vs 39 micrograms/l in nondonors, postmenopausal donors of 47 micrograms/l vs 72 micrograms/l in nondonors. S-ferritin values less than 15 micrograms/l (i.e., depleted iron stores) were observed in 31.7% of premenopausal donors vs 15.2% of nondonors, and in 7.0% of postmenopausal donors vs 2.9% of nondonors. Iron deficiency anemia (i.e., S-ferritin less than 15 micrograms/l and Hb less than 121 g/l) was seen in 2.8% of donors vs 1.5% of nondonors. Donors using oral contraceptives had higher S-ferritin, median 33 micrograms/l compared with nonusers, 22 micrograms/l, and a lower frequency of depleted iron stores, 29% vs 39%. Ideally, the frequency of phlebotomy should be adjusted according to S-ferritin as well as Hb levels. If Hb is used as single criterion for donation, only donors with predonation values greater than or equal to 124-125 g/l should be allowed to undergo phlebotomy. [ABSTRACT FROM AUTHOR]

Objective: To assess effects of iron supplementation, 66 mg elemental iron daily as ferrous fumarate, on iron status markers during normal pregnancies., Methods: Randomized, double-blind, placebo-controlled study of 119 women (62 iron-, 57 placebo -treated) and their newborns. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage (TSAT) and S-erythropoietin (S-EPO) were measured at 14-18, 24-27 weeks of gestation, prepartum, 1 and 8 weeks postpartum., Result: From 24-27 weeks gestation to 8 weeks postpartum, the iron group had higher Hb, S-ferritin and TSAT than the placebo group; prepartum, 11% had iron deficiency (ID) and 0% iron deficiency anemia (IDA) in the iron group, vs 60% and 18% in the placebo group; 8 weeks postpartum 1.6% in the iron group had ID and 1.6% IDA vs 14% and 7% in the placebo group. S-EPO levels in the iron group were lower than in the placebo group (p < 0.001). Mothers prepartum S-EPO values were correlated to newborns cord S-EPO values (p < 0.001). Newborns to iron treated mothers had higher cord S-ferritin levels than those to placebo treated mothers (p = 0.02). Newborn girls had higher cord S-ferritin levels than boys (p < 0.01). There was no impact of iron supplementation on the length of gestation, placental weight, or newborns birth weight. Birth weight was correlated only with mothers' body weight, length of gestation and placental weight., Conclusion: Iron supplementation had a "positive" impact on iron status and Hb both during pregnancy and postpartum, with a low frequency of ID/IDA and also a "positive" influence on newborns iron status.

Background/objectives: To assess vitamin D status during normal pregnancy and in the postpartum lactation period., Subjects/methods: The study comprised 141 healthy, ethnic Danish women with normal pregnancies, who were residents in Greater Copenhagen. Serum 25-hydroxy-vitamin D2+D3(25-OH-vitamin D) was measured at 18, 32 and 39 weeks' gestation and 8 weeks postpartum., Results: There was a significant increase in 25-OH-vitamin D from 18 to 32 weeks' gestation (P=0.0001) followed by a significant decrease from 32 to 39 weeks (P=0.001) as well as from 39 weeks to 8 weeks postpartum (P<0.0001). At 18, 32, 39 weeks' gestation and 8 weeks postpartum, median 25-OH-vitamin D values were 77, 98, 91, and 73 nmol/L, respectively. During pregnancy and postpartum, none of the women displayed severe vitamin D deficiency (values <13 nmol/L). Between 1.4% and 4.3% of the participants displayed moderate vitamin D deficiency (values 13-24 nmol/L), 16-19% displayed vitamin D insufficiency (values 25-50 nmol/L), 77-84% had values >50 nmol/L and 0.7-2.8% had values >200 nmol/L., Conclusions: Low vitamin D status is frequent among pregnant Danish women, especially in late pregnancy and during lactation. Median dietary intake of vitamin D in women of reproductive age was 2.4 μg/day (10-90 percentile range=1.4-5.0). The recommendations for vitamin D supplementation prior to conception, during pregnancy and lactation should be reconsidered.

Background: Based on earlier research, Rickettsia helvetica could possibly be involved in the pathogenesis of sarcoidosis. Rickettsiae are transmitted to humans by a tick vector, Ixodes ricinus; this tick is highly prevalent in Northern Europe. We aimed to investigate the association between evidence of rickettsiae and sarcoidosis in histological samples., Methods: We included formalin-fixed, paraffin-embedded mediastinal lymph node biopsies from 52 ethnic Danish patients with sarcoidosis and compared these with 50 biopsies from ethnic Danish patients with mediastinal lymphadenopathy of other causes. Samples were analysed for: (1) rickettsial DNA by real-time polymerase chain reaction (PCR) and (2) rickettsial rDNA (ribosomal DNA) by a specific fluorescence in situ hybridization technique (FISH)., Results: Rickettsia was not detected in biopsies by real-time PCR and/or FISH analyses., Conclusion: Our results do not support the hypothesis that Rickettsia is involved in the pathogenesis of sarcoidosis.

The 'iron hypothesis' claims that Fe depletion protects against IHD. The objective of the present study was to investigate the associations between serum ferritin levels and the risk of CVD and IHD in a population-based sample. A total of 2874 subjects with serum ferritin levels between 15 and 300 microg/l from the Danish part of the 'Monitoring of Trends and Determinants in Cardiovascular Disease' (DAN-MONICA) I study and the 1914 Cohort survey were followed for 10 years. Information on behavioural and socio-demographic characteristics were collected and serum ferritin levels measured. Non-fatal and fatal CVD and IHD were identified by the International Classification of Diseases diagnoses numbers. Multivariable Cox proportional hazard regression models with restricted cubic splines were performed. During the follow-up period, 310 subjects (201 men; 109 women) and 161 subjects (117 men; forty-four women) experienced CVD and IHD, respectively. Our analyses revealed no statistically significant associations between serum ferritin levels and the risk of CVD or IHD in both sexes. However, in women, the results argue for a U-shaped relationship between serum ferritin levels and CVD as well as IHD. In concordance with former prospective studies, the present results do not support the hypothesis that normal body Fe stores should play a significant role in the development of CVD.

The aim of this epidemiologic population survey was to assess the penetrance of the most frequent hemochromatosis (HFE) gene variants in ethnic Danish men. A cohort of 6,020 men aged 30-53 years was screened for HFE C282Y, H63D, and S65C variants by restriction fragment length polymorphism analysis. Subsequently, iron status markers (serum transferrin saturation, serum ferritin) were analyzed in 1,452 men. The C282Y allele was present in 5.6%, H63D in 12.8%, and S65C in 1.8% of the men. We found 23 out of 6,020 (0.38%) C282Y homozygotes, of whom two had been treated with phlebotomy. Among untreated C282Y homozygotes (n = 21) with available iron status markers (transferrin saturation n = 18, ferritin n = 16), 89% had elevated transferrin saturation >or=50%, 94% had elevated ferritin >or=300 microg/L, and 88% had elevation of both iron status markers; seven out of 16 (44%) had ferritin values >800 microg/L. One C282Y homozygote had normal iron status markers possibly due to nonexpressivity. Among C282Y/H63D compound heterozygotes (n = 66), 23% had elevated transferrin saturation, 27% elevated ferritin, and 9% elevation of both iron status markers. Among H63D/H63D homozygotes (n = 74), 15% had elevated transferrin saturation, 19% elevated ferritin, and 5.4% elevation of both iron status markers. Among C282Y/wild type (wt) heterozygotes (n = 255), 9% had elevated transferrin saturation, 9% elevated ferritin, and 1.2% elevation of both iron status markers. Among H63D/wt heterozygotes (n = 600), 8% had elevated transferrin saturation, 12% elevated ferritin, and 2% elevation of both iron status markers. None of the men with the S65C variant displayed elevation of both iron status markers. In conclusion, this study demonstrates a high penetrance of the C282Y variant in Danish men followed by the H63D variant while the S65D variant had no significant impact on iron status markers.

The blood haemoglobin concentration is one of the most frequently used laboratory parameters in clinical practice. There is evidence that haemoglobin levels are influenced by tobacco smoking. The objective of this study was to evaluate the impact of smoking and alcohol consumption on haemoglobin concentrations in apparently healthy subjects living at sea level. A retrospective, epidemiological cohort study was performed in 1984. Participants were 1,503 men and 1,437 non-pregnant women evenly distributed in age cohorts of 30, 40, 50, and 60 years. Information of smoking habits and alcohol consumption were obtained by a questionnaire. Haemoglobin was measured in the fasting state on Coulter-S. Men displayed no difference in mean haemoglobin levels in the four age groups. In women, mean haemoglobin increased gradually with age (p = 0.001). Fifty-nine percent of men and 50% of women were daily smokers. Female smokers displayed a significant positive correlation between number of cigarettes/day and haemoglobin concentrations (r = 0.12, p = 0.002). Heavy smokers (more than ten cigarettes/day) had significantly higher mean haemoglobin (1.4% higher in men, on average 3.5% higher in women) than non-smokers (p < 0.01). Smokers demonstrated a significant correlation between cigarettes/day and drinks/week in men (r = 0.24, p < 0.001) and women (r = 0.16, p < 0.001). Non-smokers displayed a significant positive correlation between drinks/week and haemoglobin concentrations in men (r = 0.14, p = 0.001) and women (r = 0.08, p = 0.05). In non-smokers, alcohol consumption >14 drinks/week and more than seven drinks/week for men and women, respectively, increased mean haemoglobin by 1.3% in men and by average 1.9% in women compared with those consuming < or =14 and less than or equal to seven drinks/week. Smokers displayed similar results. Body mass index per se had no direct influence on haemoglobin levels but had indirect positive influence in men through its correlation with tobacco smoking and alcohol consumption. Tobacco smoking has an increasing effect on haemoglobin concentrations in both genders, which is proportional to the amount of tobacco smoked. The effect appears to be more pronounced in women. Likewise, high alcohol consumption has an increasing effect on haemoglobin in both genders, being most pronounced in women. However, in clinical biochemistry, the relatively small changes in haemoglobin do not justify the use of separate reference ranges in smokers and alcohol consumers.

Rickettsia helvetica has previously been proposed as an aetiological agent in sarcoidosis. The purpose of the present study was to detect possible signs of Rickettsia infection in a Danish population of patients with sarcoidosis. Twenty-six patients with newly diagnosed sarcoidosis were prospectively enrolled in the study. The diagnosis was confirmed by biopsy in 18 and by clinical characteristics in 8 patients; 11 patients with different non-sarcoid lung diseases were recruited as controls. We obtained information regarding tick exposure and sarcoid disease manifestations by a structured interview. Evidence of rickettsial infection was assessed by an immunofluorescence assay testing for antibodies towards Rickettsia as well as specific real-time polymerase chain reaction (PCR) on lung biopsy specimens. We performed fluorescent in situ hybridization (FISH) on the biopsies to detect rickettsial and eubacterial rRNA. One sarcoidosis patient had serum rickettsial IgG antibodies above the chosen cut-off level. We found no positive rickettsial PCR or FISH analyses in any of the biopsy specimens. One sarcoid patient sample and 1 control sample contained unidentified bacteria. There was no difference in the reported frequency of tick bite between patients and controls. In conclusion, we found no evidence of Rickettsia being involved in the pathogenesis of sarcoidosis in Denmark.

Introduction: Rickettsia helvetica has been proposed as an aetiological agent in sarcoidosis., Objectives: To assess the prevalence of plasma anti-Rickettsia antibodies in a Danish population of patients with sarcoidosis and control subjects. In addition, we evaluated the presence of plasma antinuclear antibodies (ANAs)., Methods: Plasma samples from 49 consecutive patients (27 male, 22 female, median age 38 years, interquartile range 32-51 years) were compared with plasma from 51 age- and sex-matched controls (28 male, 23 female, median age 40 years, interquartile range 33-49 years), using a commercially available immunofluorescence assay testing for antibodies towards spotted fever group and typhus group Rickettsia as well as an assay for ANA. We obtained information regarding tick exposure and sarcoid disease manifestations from the medical records., Results: The prevalence of antibodies to Rickettsia in patients with sarcoidosis 1/49 (2%) was not significantly different from the prevalence in the controls 4/51 (8%). The prevalence of ANA was 2/49 (4%) in the patients and 3/51 (6%) in the controls., Conclusions: The results do not support the hypothesis that Rickettsia or ANAs should be involved in the pathogenesis of sarcoidosis. Seventy-one per cent of the patients were under treatment with prednisolone in the 3 months leading up to the blood sample. We assume that antibody-related serological methods for various reasons could be inadequate to diagnose a chronic rickettsial infection.

Background: Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility., Methods: Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61,662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model., Results: A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80)., Conclusions: This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.

The objective was to assess the frequencies of haemochromatosis (HFE) gene mutations or variants C282Y, H63D and S65C in ethnic Danes. This is a prospective epidemiologic population study. A cohort of 6,020 Danish men aged 30-50 years was screened for HFE C282Y (c845G-->A), H63D (c187C-->G) and S65C (c193A-->T) gene variants, assessed on saliva or blood samples by restriction fragment length polymorphism (RFLP) analysis. The C282Y gene variant allele was present in 5.6%, H63D in 12.8% and S65C in 1.8% of the chromosomes. In the entire series, we observed 1.4% H63D/C282Y, 0.1% S65C/C282Y and 0.4% H63D/S65C compound heterozygotes. The C282Y allele frequency in Denmark is of similar order as reported in other Scandinavian countries: Iceland 5.1%, Faeroe Islands 6.6%, Norway 6.8% and Sweden 5.8%. Also, the H63D frequency in Denmark is close to the frequencies in other Scandinavian countries: Iceland 10.9%, Faeroe Islands 15.2%, Norway 11.4% and Sweden 12.1%.

Mannose-Binding Lectin (MBL) is a prognostic marker in pulmonary diseases. Ficolins, sharing many structural and functional similarities with MBL, may also be involved in the pathogenesis of pulmonary diseases. The objectives of the study were to establish whether plasma concentrations of Ficolin-2, -3, and MBL in Danish patients with sarcoidosis and control persons differed and whether they were of prognostic significance. We retrospectively included 46 consecutive patients (26 male, 20 female) and 51 age- and sex-matched healthy control persons (28 male, 23 female). Information about the patients was obtained from their medical records. We measured plasma concentrations of Ficolin-2, -3, and MBL using ELISA. There was a significant difference in the patients' mean Ficolin-3 plasma level (14.9 microg/ml; +/-2SD: 6.7-23.1) compared with the control persons' (21.6 microg/ml; +/-2SD: 12.7-30.5). The difference was 6.7 microg/ml (95% CI: 5.0-8.4 microg/ml; p<0.001). In the patients, Ficolin-3 correlated inversely with the CD4(+)/CD8(+)-ratio (Spearman's Rho=-0.37; p=0.021; n=39). There were no significant differences in plasma concentrations of Ficolin-2 or MBL between the two groups. Ficolin-3 concentrations were lower in plasma from patients with sarcoidosis. This suggests a possible involvement of Ficolin-3 in the complex pathophysiology of sarcoidosis. However, we could not show the applicability of Ficolin plasma level measurement as a marker of disease activity or of prognostic significance in sarcoidosis.

The aim of the present study was to describe clinical features and long-term survival in childhood sarcoidosis. In total, 46 ethnic Caucasian Danish children (aged <16 yrs, 24 males) with sarcoidosis were identified in 1979-1994. In 33 (72%) children, diagnosis was verified by histology and, in the remaining 13, by clinical and radiological findings. In total, 37 subjects had a follow-up examination. Median (range) age at onset of disease was 14 (0.7-15.8) yrs and median (range) clinical follow-up was 15 (3-23) yrs after onset of disease. The median (range) age at clinical follow-up was 28 (17-30) yrs. At follow-up: 36 (78%) children recovered completely; 30 (65%) showed complete clinical regression at a median (range) 0.7 (0.6-5.9) yrs after onset of disease; two (4%) recovered with organ damage (unilateral loss of vision, abnormal chest radiograph); five (11%) still had chronic active disease with multiorgan involvement and impaired lung function; and three (7%) were deceased, due to central nervous system sarcoidosis and acute myeloid leukaemia probably caused by cytostatics. In Danish children, sarcoidosis had a favourable prognosis; the majority recovered <6 yrs after onset of disease. Some developed chronic active disease and impairment of pulmonary function, demanding continuous medical treatment. Prognosis was not related to the age at onset of disease. Erythema nodosum was associated with a good prognosis, and central nervous system involvement with a poor prognosis.

Background and Aims: In elderly Danes, reference intervals for hemoglobin (Hb) concentrations are derived from younger population groups. The aim was to examine reference intervals for Hb and cut-off limits for anemia by application of criteria for normality to a representative population of 80-year-olds., Methods: Participants in this epidemiological health survey cohort were 358 subjects (171 men) 80 years of age. A dietary survey was performed in 232 subjects. Blood samples included Hb, red cell indices, serum ferritin, serum C-reactive protein, renal and hepatic function tests. Normality criteria for Hb were: 1) values in all participants; 2) values in apparently healthy subjects; 3) values in 10-year survivors. Hb was compared with muscle strength, physical performance and diet., Results: In the entire series, median Hb was 140 g/L, 5-95 percentile 116-160 g/L in men, and 131 g/L, 5-95 percentile 114-147 g/L in women (p<0.001). The prevalence of anemia, as defined by World Health Organization (WHO) criteria, was 18% in men and 17% in women. Apparently healthy iron-replete men (n=129) and women (n=141) had median Hb of 141 g/L and 131 g/L. Median Hb levels were higher in 10-year surviving men (143 g/L) than in deceased men (139 g/L), whereas surviving and deceased women had similar median Hb (131 g/L). Hb and muscle strength were significantly correlated. Subjects with physical performance score >or=20 had a lower frequency of anemia. There was no correlation between Hb and dietary or supplemental iron intake. In men, Hb was correlated to meat consumption., Conclusions: WHO decision limits for anemia should not be lowered in 80-year-old subjects. "Optimal" Hb concentrations with respect to survival appear to be at least 140 g/L in men and 131 g/L in women. Further research should evaluate whether not only treating anemia, but also increasing Hb by using erythropoietin and hematinics, may improve functional status and survival in the elderly.

Background: Distinct mutations of the caspase activating recruitment domain 15 (CARD15) gene (also known as nucleotide-binding oligomerisation domain protein 2) on chromosome 16q are associated with the chronic granulomatous disease called Blau syndrome. Sarcoidosis is a systemic granulomatous disease, which has features in common with Blau syndrome., Aim: The aim of this study was to evaluate whether ethnic Danes with sarcoidosis have CARD15 mutations associated with Blau syndrome., Methods: Analysis of exon 4 of the CARD15 gene containing mutations associated with Blau syndrome was performed by polymerase chain reaction and sequencing of genomic DNA from 52 patients with histologically verified sarcoidosis., Results: None of the patients had mutations in CARD15 associated with Blau syndrome. Eight other variations were found in exon 4: single nucleotide polymorphism (SNP)6 in 40% of the 104 alleles examined, SNP7 in 26%, c. 1833 C > T and SNP8 in 4%, c. 2107 C > T in 2%, and c. 931 C > T, c. 1292 C > T and c. 2377 G > A in 1%. One variation was found in intron 4 (IVS4 + 10 A > C) in 3% of the alleles. The frequencies of the variations in sarcoidosis patients were not statistically significant compared with frequencies in a control group of 103 healthy subjects. The course of disease was not significantly different in patients with or without variations in CARD15 or in the 46 patients with SNP6 and/or SNP7., Conclusions: Danish sarcoidosis patients have frequent variations in CARD15 exon 4, but do not present any mutation associated with Blau syndrome. The variations found had no influence on the course of disease.

The aim of the study was to investigate whether the well-known high anemia prevalence in pregnant women from the eastern Mediterranean and Asian regions decreased when the women immigrated to a low-frequency region (Denmark). During 70 months, 1,741 pregnant immigrant women referred from primary care to an obligatory hemoglobinopathy screening were eligible for the study, as their screening was negative. To compare this group with a cohort of 205 pregnant ethnic Danish women, the groups were matched by gestational age, and a total of 406 immigrant women were included. Hemoglobin (Hb) and iron status parameters were examined in the two groups. The prevalence of anemia was higher in the immigrant group (20.0%) compared to the Danish women (4.9%) (P < 0.0001). Blood Hb concentration was 119 +/- 12 g/l (mean +/- SD) in the immigrant group compared to 122 +/- 9 g/l in the Danish group (P = 0.01). Erythrocyte mean corpuscular volume (MCV) was also lower in the immigrant group (87 +/- 7 fl vs 96 +/- 4 fl) (P < 0.0001). A total of 13.1% of the immigrant women had an MCV <80 fl (the lower reference limit) compared to 0.0% in the Danish group, and plasma iron, ferritin, and transferrin saturation values indicated iron deficiency. Conclusively, the pregnant immigrant women had significantly higher prevalence of anemia compared to pregnant women of Danish origin. It indicates the need for an alternative routine screening procedure for this population group, which should also include nutritional counselling.

Aim: To report reference intervals for haematological variables during normal pregnancy and postpartum., Material and Methods: The series comprised 434 healthy ethnic Danish women with a normal pregnancy > or =37 wk duration and a normal delivery with newborns weight >2500 g. Blood samples were obtained at 18, 32 and 39 wk gestation and at 8 wk postpartum. The following variables were analysed: Haemoglobin (Hb), haematocrit (Hct), blood erythrocyte count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white cell count, platelet count, erythrocyte folate, plasma folate, plasma cobalamin, plasma methylmalonic acid, plasma total homocysteine, serum ferritin, serum soluble transferrin receptor and plasma creatinine. Reference intervals were calculated using log(10)-transformed values (which showed normal distributions) as mean +/- 1.96 x SD., Results: The lower reference value for Hb during pregnancy was 6.45 mmol/L (105 g/L) and 7.3 mmol/L (118 g/L) postpartum. The lower reference value for Hct was 0.31 in pregnancy and 0.35 postpartum. There was a gradual decline in the lower reference value for erythrocyte folate during pregnancy and postpartum from 0.46 to 0.29 micromol/L and in plasma folate from 6 to 4 nmol/L. Lower reference value for plasma cobalamin declined during pregnancy from 96 to 71 pmol/L, but increased postpartum to 148 pmol/L. Upper reference value for plasma homocysteine increased gradually during pregnancy and postpartum from 11.0 to 20.6 micromol/L. Geometric mean serum ferritin at 18 wk gestation was 32 microg/L. Plasma creatinine values were low during pregnancy and displayed a significant increase postpartum., Conclusion: The characteristic changes occurring in haematological indices during pregnancy and postpartum are described in this study. The results may be used as reference values in the assessment of health status of pregnant women with a similar socio-economic and racial background.

Background: Mutations of the caspase-activating recruitment domain 15 (CARD15) gene on chromosome 16 are associated with chronic inflammatory granulomatous bowel disease (Crohn's disease). Sarcoidosis is a systemic granulomatous disease with unknown etiology, which shares histological features with Crohn's disease., Objectives: To evaluate whether ethnic Danes with sarcoidosis have an increased frequency of CARD15 mutations compared to healthy control subjects., Methods: Genotyping for CARD15 mutations R702W, G908R, and L1007fsinsC, also designated single nucleotide polymorphism (SNP) SNP8, SNP12 and SNP13, respectively, were performed by capillary electrophoresis single-strand confirmation polymorphism in 53 patients with histologically verified sarcoidosis and in 103 healthy controls., Results: The frequencies of CARD15 mutations in sarcoidosis patients were: SNP8, 4/106 chromosomes (3.8%); SNP12, 2/106 chromosomes (1.9%); SNP13, 2/106 chromosomes (1.9%); SNP8+SNP12+SNP13, 8/106 chromosomes (7.6%). All 8 patients were heterozygous. The frequencies in controls were: SNP8, 9/206 chromosomes (4.4%); SNP12, 2/206 chromosomes (1.0%); SNP13, 4/206 chromosomes (1.9%); SNP8+SNP12+SNP13, 15/206 chromosomes (7.3%). All controls were heterozygous. The differences were not statistically significant (p>0.05). Furthermore, the course of disease was not significantly different in the 8 patients with CARD15 mutations and the 45 patients without mutations., Conclusion: The frequency of CARD15 mutations is not increased in ethnic Danish patients with sarcoidosis, and heterozygosity for such mutations apparently has no influence on the course of disease., (Copyright (c) 2007 S. Karger AG, Basel.)

Objectives: To assess cobalamin (vitamin B(12)) status during normal pregnancy and postpartum in a longitudinal setting., Methods: This study was performed in 1995-1996. It comprised 406 healthy, pregnant Danish Caucasian women, living in Copenhagen County. Cobalamin status, i.e. plasma (P-) cobalamin, P-methylmalonic acid and P-homocysteine was measured at 18, 32 and 39 wk gestation and 8 wk postpartum during lactation., Results: P-cobalamin showed a gradual, significant decline during pregnancy (P < 0.0001) followed by a significant increase postpartum (P < 0.0001); at 18, 32, 39 wk gestation and 8 wk postpartum median values were 225, 172, 161 and 319 pmol/L, respectively. P-methylmalonic displayed a gradual, significant increase during pregnancy as well as postpartum (P < 0.001) with median values of 0.11, 0.13, 0.14, and 0.16 micromol/L, respectively. P-homocysteine demonstrated a significant increase during pregnancy and postpartum (P < 0.001). The frequency of P-cobalamin values <150 pmol/L increased during pregnancy from 15% at 18 wk to 43% at 39 wk gestation and subsequently declined to 3% postpartum., Conclusion: Low cobalamin status may occur among pregnant women, especially in late pregnancy. The recommendations for periconceptional vitamin B(12) supplementation should be reconsidered.

Objective: To assess folate and homocysteine status during normal pregnancy and postpartum in a longitudinal setting., Methods: This study, performed in 1995-1996, comprised 404 healthy pregnant Danish Caucasian women residential in Copenhagen County. Women taking folic acid tablets or vitamin B12 injections were not included. Dietary multivitamin supplements containing folic acid 100 microg or vitamin B12 1 microg, taken by 34%, were discontinued at inclusion. Participants had normal renal function. Folate status [erythrocyte (Ery-) folate, plasma (P-) folate, P-homocysteine] was measured at 18, 32 and 39 wk of gestation and 8 wk postpartum when the women were lactating., Results: Through 18, 32 and 39 wk of gestation and postpartum, P-folate demonstrated a significant fall: median values were 14.4, 10.2, 9.3 and 8.9 nmol/L, respectively (P < 0.0001). The prevalence of low P-folate <6 nmol/L increased during pregnancy from 0.7% to 19.0% postpartum (P < 0.0001). Ery-folate displayed a similar, significant fall: median value was 0.84, 0.75, 0.65 and 0.55 micromol/L, respectively (P < 0.0001). The prevalence of low Ery-folate <0.40 micromol/L increased during pregnancy from 0.5% to 17.2% postpartum (P < 0.0001). P-homocysteine demonstrated a significant increase: median value was 6.4, 7.0, 7.7 and 10.8 micromol/L, respectively (P < 0.0001). The prevalence of P-homocysteine >13 micromol/L increased during pregnancy from 0.7% to 20.8% postpartum (P < 0.0001). The prevalence of low folate status (defined as P-folate <6 nmol/L and P-homocysteine >13 micromol/L) was 0%, 0%, 1.2%, and 8.4% at 18, 32 and 39 wk of gestation and 8 wk postpartum, respectively., Conclusion: Low folate status occurs among Danish pregnant women, especially in late pregnancy and postpartum during lactation. Despite new guidelines for folic acid supplement since 1997, only 13% of pregnant women followed the guidelines in 2003. The official recommendations for periconceptional folic acid supplement should be reconsidered and reinforced.

Background: The biological function of rubidium (Rb) is unknown, but this alkali metal probably has a normal biologic role., Objective: To measure the content of Rb in liver tissue samples from Greenlandic Inuit using X-ray fluorescence spectrometry, and compare the results with those obtained in liver samples from ethnic Danes., Study Design: Observational, descriptive survey on environmental pathology., Methods: The setting was related to forensic medicine and hospitalised care in Nuuk, Ilulissat and Copenhagen. Normal liver tissue was obtained at autopsy from 50 Greenlandic Inuit (27 men) with a median age of 61 years (range 23-83) and from 42 Danes (31 men) with a median age of 38 years (range 16-83)., Results: Liver Rb content in Inuit was not significantly different compared with Danes. There was no significant gender difference in liver Rb content either in Inuit or in Danes. The content of Rb given as median (5-95 percentile) was 0.1837mmol/kg dry liver (0.1041-0.3147) in Inuit, and 0.1965mmol/kg dry liver (0.0799-0.2815) in Danes (p=0.6). There was an inverse correlation between liver Rb content and age in Inuit (r(s)=-0.45, p=0.002) but not in Danes. Median hepatic Rb index (Rb content in micromol/kg dry weight divided by age in years) in Inuit was 3.05 and in Danes 4.21 (p=0.02). The correlations between liver Rb and liver potassium content were: Inuit r(s)=0.28, p=0.07; Danes r(s)=0.25, p=0.08; combined series r(s)=0.34, p=0.01., Conclusions: Inuit have liver Rb levels, which are quite similar to the levels found in Danes. In Inuit, liver Rb content appears to decrease with age.

Objective: To review the 13-year clinical experience of a single center's adult lung transplantation program., Methods: From January 1992 to December 2003, 369 lung transplantations were performed on 362 patients. Single lung transplantation was performed in 234 cases, double lung transplantation in 113 cases (comprising en-bloc double lung transplantation in 44 cases and bilateral sequential lung transplantation in 69 cases), heart-lung transplantation in 21 cases, and lobe of lung transplantation in 1 case. Recipient diagnoses included chronic obstructive pulmonary disease (COPD) (n = 175), alpha1 antitrypsin (alpha1AT) deficiency (n = 86), cystic fibrosis (n = 36), pulmonary fibrosis (n = 20), Eisenmenger syndrome and secondary pulmonary hypertension (n = 24), primary pulmonary hypertension (n = 8), sarcoidosis (n = 7), silicosis (n = 4), bronchiectasis (n = 1), and graft-vs-host disease (n = 1)., Results: For patients surviving to discharge, the median duration of the intensive care unit stay was 3 days (1-67), and the median duration of the post-operative hospital stay was 37 days (16-144). Mortality for the entire series was 6% at 30 days and 10% at 90 days. The main causes of post-operative inpatient death were primary graft failure (41%), sepsis (29%), cardiac (15%), and hemorrhage (9%). The 1-, 3-, 5-, and 10-year actuarial survival rates for the entire series was 81%, 68%, 63%, and 36%, respectively. There were no significant differences in survival between types of transplant. No significant differences in survival were seen between alpha(1)AT deficiency and COPD patients after stratifying for age. Cox regression analysis demonstrated that age 60 years or older, donor age 50 years or older, and a recipient pre-operative body mass index of 25 or higher were independent predictors of poor survival., Conclusions: This center has 1-, 3-, and 5-year survival rates comparable to other high volume centers. Recipient age, pre-operative body mass index, and donor age significantly influence outcome after lung transplantation.

Objectives: To measure the quantity of lead (Pb) in liver tissue samples from Greenlandic Inuit, and compare the results with those obtained in Caucasian Danes., Study Design: Observational, descriptive survey on environmental pathology., Methods: The setting was related to forensic medicine and hospitalised care in Nuuk, Ilulissat and Copenhagen. Participants were 50 Greenlandic Inuit (27 men) with a median age of 61 years (range 23-83) and 74 Danes (44 men) with a median age of 60 years (range 15-87). Liver tissue samples (normal by macroscopic and microscopic examination) were obtained at autopsy. Total liver lead content was measured by X-ray fluorescence spectrometry with a detection limit of 0.05 micromol/kg dry weight., Results: In the entire series, Inuit had higher liver lead contents than Danes (p < 0.0001). Inuit men had higher liver lead content than Inuit women (p = 0.02). In Danes, men tended to have higher liver lead contents than women, but the difference was insignificant. The median (5-95 percentile) lead content was 14.96 micromol/kg dry liver (4.83-74.80) in Inuit, and < 0.05 micromol/kg dry liver (< 0.05-29.44) in Danes. All Inuit had liver lead contents above the detection limit, whereas 60 Danes (81%) had liver lead content below the detection limit. There was a positive correlation between liver lead content and age in both Inuit (rs = 0.46, p = 0.002) and Danes (n = 14; rs = 0.71, p = 0.01). Inuit had higher hepatic lead indices (liver lead content divided by age) than Danes (p < 0.0001). In Inuit, median hepatic lead index was 0.258, being higher in men than in women (p = 0.02). In Danes, the median hepatic lead index was 0.001, again higher in men than in women (p = 0.03)., Conclusions: Our results show a gender-related difference in hepatic lead content, i.e. Inuit men have higher liver lead contents than women. Furthermore, Inuit men and women have higher hepatic lead contents than Danish men and women. In both Inuit and Danes, the liver lead content increases with age. One reason for the high lead levels in Inuit may be ingestion of seabirds contaminated by lead shot.

The Danish Nutrition Council has examined the latest scientific literature on nutrition during pregnancy to evaluate the basis for the existing official recommendations. The recommendation to overweight women to gain only eight kilo should be accompanied with a recommendation to lose weight pre-conceptionally. Individualised recommendations should be provided in the prevention of iron deficiency, and the recommendation for calcium should include information on quantity. The recommendation of periconceptional folic acid supplementation does not benefit unplanned pregnancies. Arguments exist for adding a recommendation for vitamin D.

Objective: To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy., Methods: A randomized, double-blind intention-to-treat study comprising 427 healthy pregnant women allocated into four groups taking ferrous iron (as fumarate) in doses of 20 mg (n = 105), 40 mg (n = 108), 60 mg (n = 106), and 80 mg (n = 108) from 18 weeks of gestation. Iron status markers [hemoglobin (Hb), serum ferritin, and serum soluble transferrin receptor (sTfR)] were measured at 18 weeks (inclusion), 32 weeks, and 39 weeks of gestation and 8 weeks postpartum. Side effects of iron supplements were recorded. Iron deficiency was defined as serum ferritin <13 microg/l and iron deficiency anemia as serum ferritin <13 microg/l and Hb <5th percentile in iron replete pregnant women., Results: There were no significant differences between variables in the four groups at inclusion. At 32 and 39 weeks of gestation, group 20 mg had significantly lower median serum ferritin (13 and 16 microg/l) than group 40 mg (17 and 21 microg/l), group 60 mg (18 and 23 microg/l), and group 80 mg (21 and 24 microg/l) (p < 0.0001). At 32 and 39 weeks of gestation, group 20 mg had a significantly higher prevalence of iron deficiency (50 and 29%) than group 40 mg (26 and 11%), group 60 mg (17 and 10%), and group 80 mg (13 and 9%) (p < 0.001). The prevalence of iron deficiency anemia at 39 weeks of gestation was significantly higher in group 20 mg (10%) than in group 40 mg (4.5%), group 60 mg (0%), and group 80 mg (1.5%) (p = 0.02). At 32 weeks of gestation, mean Hb in group 20 mg was lower than in group 80 mg (p = 0.06). There were no significant differences in iron status (ferritin, sTfR, and Hb) between group 40, 60, and 80 mg. Postpartum, group 20 mg had significantly lower median serum ferritin than group 40, 60, and 80 mg (p < 0.01). The prevalence of postpartum iron deficiency anemia was low and similar in the four groups. The frequency of gastrointestinal symptoms was not significantly different in the four iron supplement groups and thus not related to the iron dose., Conclusion: In Danish women, a supplement of 40 mg ferrous iron/day from 18 weeks of gestation appears adequate to prevent iron deficiency in 90% of the women and iron deficiency anemia in at least 95% of the women during pregnancy and postpartum.

In Denmark, the intake of dietary iron has decreased since 1987, when the mandatory iron fortification of flour (30 mg carbonyl iron/kg) was stopped. Since there have been no studies of iron status in elderly Danes after the abolishment of iron fortification, there is a need to assess actual iron status in the elderly population. The objective was to evaluate iron status and the relationship with food composition and dietary and supplemental iron intake in an elderly population in Copenhagen County. Participants in this health examination survey were 358 subjects (171 men, 187 women) 80 years of age from a 1914 cohort study. Blood samples included serum ferritin and hemoglobin (Hb). A dietary survey was performed in 232 subjects (120 men, 112 women) using a dietary history method. Median serum ferritin was 100 microg/l in men and 78 microg/l in women ( p<0.001). Ferritin concentrations <16 microg/l (i.e., depleted iron stores) were found in three men (2%) and in ten women (5%). Median Hb was 140 g/l in men and 131 g/l in women ( p<0.001). Three subjects (0.84%) had iron deficiency anemia (i.e., ferritin <13 microg/l and Hb <5th percentile for iron-replete subjects (121 g/l in men, 114 g/l in women). Ferritin concentrations >300 microg/l (i.e., iron overload) were found in 15 (9%) men and in 5 (3%) women. Median dietary iron intake was higher in men (8.7 mg/day) than in women (7.3 mg/day) ( p<0.001). Serum ferritin was positively correlated to dietary intake of iron, meat, and alcohol and to body mass index in men. Serum ferritin displayed a negative correlation to the consumption of tea. The use of vitamin-mineral supplements containing iron had no influence on iron status. Dietary intake of iron and/or the bioavailability of dietary iron were adequate to maintain a favorable iron status in 80-year-old subjects displaying a low prevalence of iron deficiency and a moderate prevalence of iron overload.

The content of selenium in normal liver tissue samples from Greenlandic Inuit was measured and the results compared with those obtained in normal liver tissue samples from Danes. Normal liver tissue samples were obtained at autopsy from 50 Greenlandic Inuit (27 men, 23 women) with a median age of 61 years (range 23-83) and from 74 Danes (44 men, 30 women) with a median age of 60 years (range 15-87). Total liver selenium content was measured by X-ray fluorescence spectrometry. The content of selenium (median) was in Inuit 26.6 micromol/kg dry liver (5-95 percentile: 15.2-49.4) and in Danes 17.7 micromol/kg dry liver (5-95 percentile: < 3.8-36.5) (p < 0.0001). Liver selenium content displayed no significant gender difference, either in Inuit or Danes. In Inuit men, there was a negative correlation between liver selenium content and age (rs = -0.39, p < 0.05), whereas Danish men displayed a positive correlation between liver selenium content and age (rs = 0.37, p = 0.02). There was no correlation in Inuit or Danish women. In Inuit, the median hepatic selenium index (liver selenium content divided by age) was 0.48 and in Danes 0.33 (p = 0.001). There was an inverse correlation between hepatic selenium index and age both in Inuit (rs = -0.77, p < 0.0001) and in Danes (rs = -0.47, p < 0.0001). In conclusion, Inuit had a higher liver content of selenium and a higher hepatic selenium index compared with Danes. The more favourable selenium status is due to a higher nutritional selenium intake with fish and meat from sea mammals.

Background and Objectives: From 1954 to 1986, flour in Denmark was fortified with 30 mg carbonyl iron per kilogram. This mandatory enrichment of cereal products was abolished in 1987. The aim was to evaluate iron status in the Danish female population before and after abolishment of iron fortification., Methods: Iron status, serum ferritin and haemoglobin, was assessed in population surveys in 1983-1984 comprising 1221 Caucasian women (1089 non-blood-donors, 130 donors) and in 1993-1994 comprising 1261 women (1155 non-blood-donors, 104 donors) equally distributed in age cohorts of 40, 50, 60 and 70 yr., Results: In the 1984 survey, median ferritin values in the four age cohorts in non-blood-donors were 44, 57, 84 and 80 microg/L, and in the 1994 survey 40, 67, 97 and 95 microg/L, respectively. In 1984, premenopausal women had median ferritin of 43 microg/L and in 1994 of 39 microg/L (NS). In 1984, postmenopausal women had median ferritin of 75 microg/L and in 1994 of 93 microg/L (P < 0.0001). The prevalence of depleted iron stores (ferritin < 16 microg/L) was not significantly different in 1984 and 1994 either in premenopausal or in postmenopausal women. The prevalence of small + depleted iron stores (ferritin 300 microg/L) was unchanged in premenopausal women and had increased from 2.4% to 5.5% in postmenopausal women (P = 0.003). During the study period there was an increase in body mass index both in premenopausal and postmenopausal women (P = 0.06 and P = 0.008). Postmenopausal women displayed an increase in alcohol consumption (P < 0.0001) and a decrease in tobacco smoking (P < 0.001). In premenopausal women, there was a marked increase in the use of non-steroid anti-inflammatory drugs (P < 0.0001) in the study period, while this was unchanged in postmenopausal women. In premenopausal blood donors, median ferritin decreased from 1984 to 1994 (36 microg/L vs. 24 microg/L, P < 0.06). In postmenopausal blood donors, ferritin was not significantly different from 1984 to 1994 (50 microg/L vs. 41 microg/L, P = 0.15)., Conclusion: Abolition of iron fortification reduced the median dietary iron intake in Danish women from 12 to 9 mg/d. Despite the absence of food iron fortification, from 1984 to 1994, body iron stores were unchanged in premenopausal women, whereas iron stores and the prevalence of iron overload in postmenopausal women had increased significantly. The reason appears to be the changes in dietary habits with a lower consumption of dairy products and eggs, which inhibit iron absorption, and a higher consumption of alcohol, meat and poultry, containing heme iron and enhancing iron absorption.

Background and Aim: To evaluate the incidence of sarcoidosis in Denmark 1980-1994., Methods: Patients with a diagnosis of sarcoidosis were identified from the Danish National Patient Registry. The file contained information about the year in which the diagnosis was reported, gender, age, and residential county., Results: 5536 persons (2816 men) with sarcoidosis were registered. Median age in men was 38 years, in women 45 years. The male/female incidence ratio was 1.06. The incidence (per 100,000 person years) declined gradually from 8.1 in 1980-1984 to 6.4 in 1990-1994. The overall incidence in 1980-1994 was 7.2. Incidence rates 1980-1994 increased from eastern to western parts of Denmark: Zealand 5.7, Funen 6.8, and Jutland 8.4. The peak incidence in men occurred at 30-34 years of age (14.8). Women displayed two similar peak incidences at 25-29 years of age (10.5) and at 65-69 years of age (11.0)., Conclusion: Incidence rates in the present study are lower compared with previous mass-screening surveys showing an incidence rate of 13.8 (in persons examined). Peak incidences occurred at higher ages in both men and women. Previous surveys showed peak incidences at 20-25 years in men and at 25-30 years and 50 years in women. The overall incidence of sarcoidosis in Denmark ranges from 7-10 per 100,000 person years. With 5,500,000 residents, the expected number of new cases of sarcoidosis in Denmark is between 385 and 550 per year.

Objective: To assess the sero-prevalence of IgG antibodies to Helicobacter pylori (H. pylori) in Greenlanders and compare with the sero-prevalence in Caucasian Danes., Methods: 71 randomly recruited indigenous Greenlanders (29 men) with a median age of 39 years (range 22-76), living in the capital, Nuuk, and the town of Ilulissat, and participating in a population survey carried out in 1993-1994. The results were compared with those obtained in a 1983-1984 population survey in Copenhagen County, comprising 2794 Caucasian Danes (1425 men) with a median age of 41 years (range 30-60). Serum IgG antibody levels to H. pylori were determined by an indirect enzyme-linked immunosorbent assay in 1995 and categorised as negative, borderline (equivocal), or positive., Results: Greenlanders: 48.3% of men and 45.2% of women had positive serum IgG antibody levels to H. pylori In the entire series, 46.5% had positive IgG antibody levels, 25.4% displayed borderline antibody levels and 28.2% had negative antibody levels. There were no age, or gender differences concerning the prevalences of the three H. pylori IgG antibody subgroups. Danes: 25.6% of men, and of women, had positive IgG antibody levels against H. pylori. In the entire series, 25.6% had positive IgG antibody levels, 19.0% displayed borderline antibody levels and 55.4% had negative antibody levels. There was no gender difference concerning the sero-prevalence of IgG antibodies, but the sero-prevalence increased significantly with age. The prevalence of positive serum IgG antibodies against H. pylori was markedly higher in Greenlanders than in Danes (p < 0.0001)., Conclusion: Indigenous Greenlanders have a significantly higher infection rate with H. pylori than Danes. The results suggest that Greenlanders become infected with H. pylori early in life.

Background and Objectives: From 1954 to 1987, flour in Denmark was fortified with 30 mg carbonyl iron per kg. This mandatory fortification was abolished in 1987. The aim of this study was to compare iron status in Danish men before and after abolition of iron fortification., Methods: Iron status (serum ferritin, haemoglobin), was assessed in population surveys in Copenhagen County during 1983-84 comprising 1324 Caucasian men (1024 non-blood-donors, 300 blood donors) and in 1993-94 comprising 1288 Caucasian men (1103 non-blood-donors, 185 donors), equally distributed in age cohorts of 40, 50, 60 and 70 yr., Results: In the 1984 survey median serum ferritin values in the four age cohorts in non-blood-donors were 136, 141, 133 and 111 microg/L, and in the 1994 survey 177, 173, 186 and 148 microg L(-1), respectively. The difference was significant in all age groups (P<0.001). There was no significant difference between the two surveys concerning the prevalence of small iron stores (ferritin 16-32 micro g L(-1)), depleted iron stores (ferritin <16 microg L(-1)) or iron-deficiency anaemia (ferritin <13 microg L(-1) and Hb <5th percentile for iron-replete men). However, from 1984 to 1994, the prevalence of iron overload (ferritin >300 microg L(-1)) increased from 11.3% to 18.9% (P<0.0001). During the study period there was an increase in body mass index (P<0.0001), alcohol consumption (P<0.03) and use of non-steroid anti-inflammatory drugs (NSAID) (P<0.0001), and a decrease in the use of vitamin-mineral supplements (P<0.04) and in the prevalence of tobacco smoking (P<0.0001). In contrast, median ferritin in blood donors showed a significant fall from 1984 to 1994 (103 vs. 74 micro g L(-1), P<0.02)., Conclusion: Abolition of iron fortification reduced the iron content of the Danish diet by an average of 0.24 mg MJ(-1), and the median dietary iron intake in men from 17 to 12 mg d(-1). From 1984 to 1994, body iron stores and the prevalence of iron overload in Danish men increased significantly, despite the abolition of food iron fortification. The reason appears to be changes in dietary habits, with a lower consumption of dairy products and eggs, which inhibit iron absorption, and a higher consumption of alcohol, meat, and poultry, containing haem iron and enhancing iron absorption. The high prevalence of iron overload in men may constitute a health risk.

The object was to analyze, in a nationwide survey, the incidence and course of hereditary hemochromatosis in relation to the degree of iron overload and the presence of organ damage. The study included 179 Danish Caucasian patients with clinically overt hemochromatosis diagnosed between 1948 and 1985. A cohort of 158 patients was followed for a median of 8.5 years (range: 0.2-29.5). From 1951 to 1975, the yearly relative incidence rate was constant: 0.58/100,000 persons >20 years of age. From 1981 to 1985, the yearly relative incidence rate rose to 1.40/100,000 persons >20 years of age. Survival was reduced in the entire series when compared with a matched control population ( p<0.0001). There was a steady increase in survival from 1948 to 1985 ( p<0.002). Survival was significantly reduced in patients with liver cirrhosis and/or diabetes mellitus ( p<0.01). In contrast, survival in patients without cirrhosis or diabetes was similar to rates expected. Survival in patients with arthropathy was higher than in patients without joint affection ( p<0.004). Patients adequately treated with phlebotomy ( n=66) had a higher survival than inadequately treated patients ( n=62; p<0.0001). Adequately treated patients with cirrhosis and/or diabetes had better survival than inadequately treated patients with similar organ damage ( p<0.001). The main causes of death were hepatic failure due to cirrhosis (32.0%) and cirrhosis with liver cancer (23.1%). Sharpened diagnostic awareness has improved early diagnosis and increased the diagnostic frequency of clinical hemochromatosis. Adequate phlebotomy treatment was the major determinant of survival and markedly improved prognosis. Early detection and treatment of this common iron overload disorder is crucial and can completely prevent any excess mortality caused by hemochromatosis.

Objective: To compare haemoglobin concentrations in Greenlanders and Danes., Methods: Haemoglobin was measured in a population survey in 1993-1994 comprising 234 indigenous Greenlandic individuals (115 men) aged 19-82 yr. and in Copenhagen County 1983-1984 comprising 2804 Caucasian Danes (1444 men) aged 30-60 yr. The Greenlandic participants were residents in the capital Nuuk (n=70), the town Ilulissat (n=74), and four settlements in the Uummannaq district (n=90). The significance of differences was assessed by Student's t-test, and the xi2-test. Correlations were assessed by Spearman's correlation coefficient (rs)., Results: Greenlanders: Haemoglobin levels were not correlated with age or consumption of traditional foods, and were not significantly different in the three residential areas. Mean haemoglobin was higher in men, 146+/-9.6 (SD) g/L, than in women, 132+/-9.6 g/L (p<0.0001). Mean haemoglobin in iron-replete men with serum ferritin >32 microg/L (n=104) was 146+/-9.3 g/L, and in iron-replete women (n=68) 133+/-10.4 g/L (p<0.0001). The 5th percentile for haemoglobin in iron-replete men was 133 g/L (8.3 mmol/L) and in women 118 g/L (7.3 mmol/L). The prevalence of iron deficiency anaemia (i.e. ferritin <13 microg/L and Hb <5th percentile for iron-replete men and women) was 0% in men, 2.78% in women < or =50 yr of age and 0% in women >50 yr of age. Danes: Mean haemoglobin in men was 154+/-10.0 g/L and in women 138+/-10.4 g/L (p<0.0001). Haemoglobin in iron-replete men (n=1379) (i.e. serum ferritin >32 microg/L) was 154+/-10.7 g/L, and in iron-replete women (n=1003) 140+/-9.6 g/L (p<0.0001). Mean haemoglobin was lower in premenopausal than in postmenopausal women (p<0.0001). The 5th percentile for haemoglobin in iron-replete men was 137 g/L (8.5 mmol/L) and in women 124 g/L (7.7 mmol/L). The prevalence of iron deficiency anaemia (i.e. ferritin <13 microg/L and Hb <5th percentile for iron replete men and women) was 0% in men, 1.92% in women < or =50 yr of age and 0% in women >50 yr of age., Conclusion: Haemoglobin concentrations in Greenlanders were significantly lower than in Danes both in men (p<0.0001) and in women (p<0.0001). Delta(mean haemoglobin) in men was 8.0 g/L (0.5 mmol/L) and in women 6.2 g/L (0.4 mmol/L). Variations in haemoglobin levels may be due to genetic differences.

The aim of the study was to measure the content of zinc (Zn) in liver tissue samples from Greenlandic Inuit using X-ray fluorescence spectrometry, and compare the results with those obtained in liver samples from Danes. Normal liver tissue samples was obtained at autopsy from 50 Greenlandic Inuit (27 men) with a median age of 61 years (range 23-83) and from 74 Danes (44 men) with a median age of 60 years (range 15-87). In the entire series, liver zinc content in Inuit was not significantly different compared with Danes. There was no significant gender difference in liver zinc content either in Inuit or in Danes. The content of zinc given as median (5-95 percentile) was in Inuit 3.809 mmol/kg dry liver (2.355-7.406), and in Danes 3.992 mmol/kg dry liver (2.499-8.645). There was a significant, positive correlation between liver zinc content and age in Danish women (r(s) = 0.43, p = 0.02), which could not be demonstrated in Danish men or in Inuit. Median hepatic zinc index (zinc content in mmol/kg dry weight divided by age in years) in Inuit was 0.073, and in Danes 0.080 (p = 0.3) without any significant difference between the two genders. In Inuit and Danes there was an inverse correlation between hepatic zinc index and age both in the two genders and in the entire series: Inuit: r(s) = -0.62, p < 0.0001; Danes: r(s) = -0.70, p < 0.0001. The results indicate that Inuit have liver zinc levels, which are similar to those found in Danes.

Iron status, i.e. serum ferritin and haemoglobin (Hb) levels, was assessed in a population survey in 1994 (Dan-Monica 10) comprising 1319 Caucasian Danish women in age cohorts of 40, 50, 60 and 70 years. In the entire series, ferritin levels increased significantly from 40 years to 60 years of age. The prevalence of small iron stores (ferritin 16-32 microg/l), depleted iron stores (ferritin < 16 microg/l) and of iron deficiency anaemia (ferritin < 13 microg/l and Hb < 121 g/l) decreased steadily with age. Blood donors (n = 109) had lower ferritin levels than non-donors (P<0.0001). Ferritin levels in donors were inversely correlated with the cumulated number of lifetime phlebotomies (r(s) = -0.25, P<0.01). Ferritin levels in non-donors (n = 1208) were low in 40-year-old women (median 40 microg/l) and increased to a median of 95 microg/l in 60- and 70-year-old women (P<0.0001). In non-donors 40 years of age, the prevalence of small iron stores was 40.4%, the prevalence of depleted iron stores 10.8% and the prevalence of iron deficiency anaemia 2.16%. The prevalence of iron overload (ferritin >300 microg/l) was 1.54%. Ferritin levels in 60- and 70-year-old non-donors were correlated with the body mass index (r(s) =0.11, P=0.01). Ferritin levels in 50- to 60-year-old non-donors were correlated with alcohol intake (r(s)=0.23, P<0.0001). In the entire series, 37.5% of non-donors took supplemental ferrous iron (median 14 mg iron per day). Iron supplements had a significant positive influence on iron status in 40-year-old premenopausal non-donors but no effect in postmenopausal women or in donors. Non-donors (n = 170) treated with acetylsalicylic acid had lower ferritin levels (median 55 microg/l) than non-treated (n = 1038; median 75 microg/l) (P<0.0001). Compared with the Dan-Monica 1 iron status survey in 1984, the prevalence of iron deficiency and iron deficiency anaemia was unchanged, whereas the prevalence of iron overload displayed a slight increase. The 1987 abolition of the mandatory iron fortification of flour apparently had no negative effect on iron status.

The purpose of this study was to measure the content of iron (Fe) in liver tissue samples from urbanized Greenlandic Inuit using X-ray fluorescence spectrometry, and compare the results with those obtained in liver tissue samples from urbanized Danes. Normal liver tissue samples were obtained at autopsy from 50 Greenlandic Inuit (27 men, 23 women) with a median age of 61 years (range 23-83) and from 72 Danes (42 men, 30 women) with a median age of 62 years (range 15-87). In the entire series, there was no significant difference between liver iron in Inuit compared with Danes. Likewise, there was no significant gender difference concerning liver iron content, either in Inuit or in Danes. The median iron content (with 5-95 percentile) in Inuit was 17.23 mmol/kg dry liver (5.80-91.80) and in Danes 16.51 mmol/kg dry liver (7.83-39.05). However, when stratified according to age, a trend was revealed showing that Inuit men and women < or = 50 years had a lower liver iron content than Danes (p = 0.05 and p = 0.08) whereas Inuit men and women > 50 years had a higher liver iron content than Danes (p = 0.18 and p = 0.02). There was a significant correlation between liver iron content and age in both Inuit men (rs = 0.49, p = 0.01) and in women (rs = 0.64, p = 0.003), but not in Danes. In Inuit, the median hepatic iron index (liver iron content divided by age) was 0.33 in men and 0.32 in women. The median estimated iron content in the whole liver was 6.54 mmol (365 mg) in Inuit men and 5.41 mmol (302 mg) in Inuit women (p = 0.6). There was no correlation between hepatic iron index and age. In Danes, the median hepatic iron index was 0.46 in men and 0.29 in women (p = 0.01). There was a significant inverse correlation between hepatic iron index and age in the two genders and in the entire series (rs = -0.71, p = 0.0001). The results indicate that young and middle-aged urbanized Inuit have slightly smaller iron stores than urbanized Danes, whereas elderly Inuit have higher iron stores than Danes. In Danes, iron stores plateau at 30 to 40 years of age in men and some years after the menopause in women. In Inuit, iron stores continue to increase in old age, probably to due a lifelong dietary intake of haem iron.

We evaluated the influence of Helicobacter pylori (H. pylori) infection assessed by the levels of H. pylori serum IgG-antibodies, on iron status (serum ferritin and haemoglobin) in 2794 Danes (1425 men), aged 30-60 years. The seroprevalence of H. pylori antibodies increased with age (p < 0.01). Median serum ferritin levels were significantly lower in seropositive than in seronegative men and postmenopausal women (men 114 micrograms/L vs. 120 micrograms/L, p = 0.01; premenopausal women 37 micrograms/L vs. 40 micrograms/L, p = 0.13; postmenopausal women 63 micrograms/L vs. 77 micrograms/L, p = 0.02). Seropositive subjects had a higher prevalence of iron deficiency (serum ferritin < 15 micrograms/L) than seronegative subjects. H. pylori infection has a negative influence on iron status. We hypothesize that this may be caused by increased blood losses from the gastric mucosa.

This study examined trends in iron status in adolescents. Serum ferritin was measured in 1986 and 1992 in 319 Danes (161 males) stratified into 5 groups: I. median age 9 yr in 1986 vs. 15 yr in 1992; II. 11 vs. 17 yr; III. 13 vs. 19 yr; IV. 15 vs. 21 yr; V. 17 vs. 23 yr. Males in group I demonstrated no change in ferritin or estimated iron stores in mg/kg; groups II-V displayed an increase in iron status parameters. All groups showed an increase in estimated total iron stores. Changes in iron status parameters were inversely correlated with height velocity in group III, and positively correlated with height velocity in group V. Females in age groups I and II demonstrated a fall in ferritin and estimated iron stores in mg/kg in association with menarche; values were unchanged in groups III and IV, and increased in group V. All groups showed an increase in estimated total iron stores. Changes in iron status parameters were inversely correlated with height velocity in groups I and II. In conclusion, ferritin levels in adolescents display great variation during growth spurt and at menarche. Changes in ferritin showed no consistent association with growth velocity. In both genders, estimated total iron stores increased with age.

Iron status, S-ferritin, and hemoglobin (Hb) were assessed in a population survey in 1994 (DAN-MONICA 10) comprising 1332 Caucasian Danish men equally distributed in age cohorts of 40, 50, 60 and 70 years. Blood donors (n=186) had lower S-ferritin, median 76 microg/l, than nondonors, median 169 microg/l (p<0.0001). S-ferritin in donors was inversely correlated with the number of phlebotomies (r(s)=-0.57, p<0.0001). S-ferritin in nondonors (n=1146) was similar in men 40-60 years of age, median 176 microg/l, and subsequently decreased at 70 years of age to a median of 146 microg/l (p=0.01). In the entire series, the prevalence of small iron stores (S-ferritin 16-32 microg/l) was 2.7%, that of depleted iron stores (S-ferritin <16 microg/l) 0.45%, and that of iron deficiency anemia (S-ferritin <13 microg/l and Hb <129 g/l) 0.15%. Among nondonors, the prevalence of iron overload (S-ferritin >300 microg/l) was 20%. S-ferritin in nondonors correlated with body mass index (r(s)=0.19, p=0.0001) and with alcohol intake (r(s)=0.26, p=0.0001). In the entire series, 28% of the subjects took supplemental iron (median 14 mg ferrous iron daily). Iron supplements had no influence on iron status. Nondonors (n=170) treated with acetylsalicylic acid had lower S-ferritin, median 136 microg/l, than nontreated, median 169 microg/l (p<0.001) and those treated with H(2)-receptor antagonists (n=30) had lower S-ferritin, median 142 microg/l, than nontreated, median 171 microg/l (p<0.04). Compared with the DAN-MONICA 1 iron status survey of Danish men in 1984, the prevalences of iron depletion and iron deficiency anemia are unchanged whereas the prevalence of iron overload has increased significantly. In Denmark, iron fortification of flour was abolished in 1987. This apparently had no negative effect on iron status in men.

Background: Health authorities recommend that populations consume a diet providing sufficient iron, and in order to prevent iron deficiency, a number of countries have fortified certain foods with iron. In Denmark, flour was fortified with iron from 1954 until 1987, at which time the mandatory fortification was stopped. This study examines the effect of iron fortification on iron status by comparing the intake of iron with serum ferritin over time and in relation to the removal of flour fortification., Methods: In a cohort of 238 Danish men and women, at baseline ages 35-65 years, dietary intake and serum ferritin were measured, first in 1987/1988 and again in 1993/1994., Results: In 1987/1988 the fortification may have supplied up to 25% of total iron intake, and without this enrichment some 35% of the men and 73% of the women may have had iron intakes lower than 10 mg/day. Assuming that no flour was enriched, iron intake was constant during the 6-year study period. Despite this, after flour fortification was stopped in 1987, serum ferritin increased among both men and postmenopausal women., Conclusions: Considering that mandatory iron fortification of flour affects the entire population, including subjects who are at risk for chronic diseases because of too-high iron stores, the decision to stop the mandatory fortification in Denmark seems to have been well-founded., (Copyright 1999 American Health Foundation and Academic Press.)

Objectives: The aim was to examine the relationships between serum ferritin and risk factors for ischaemic heart disease (physical activity, body mass index, tobacco smoking, alcohol consumption, serum total cholesterol, serum triglycerides, serum high-density lipoprotein (HDL) cholesterol, systolic and diastolic blood pressures)., Design: Epidemiological population survey performed at the Copenhagen County Centre for Prevention of Disease in 1982-84., Subjects: The participants were selected at random from the census register and comprised 2235 healthy Caucasian Danes, all non-blood-donors (1044 men and 1191 women), in cohorts of 30, 40, 50 and 60 years of age. The participants gave a detailed medical history and had a clinical examination including blood samples., Main Outcome Measures: In both men and women, all risk factors displayed a significant increase with age. In men aged 40-60 years, significant positive associations were found between serum ferritin and the following risk factors: body mass index, alcohol intake, serum triglycerides, and systolic and diastolic blood pressures. There was a significant negative association between serum ferritin and tobacco smoking. There was no association between serum ferritin and physical activity, serum total cholesterol or serum HDL cholesterol. In women aged 40-60 years, significant positive associations were found between serum ferritin and the following risk factors: body mass index, alcohol intake and serum triglycerides. There was no association between serum ferritin and physical activity, tobacco smoking, serum total cholesterol, serum HDL cholesterol or blood pressure., Conclusions: Associations were found between serum ferritin and some risk factors for ischaemic heart disease in men and women. The clinical significance of these findings remains to be clarified. One may hypothesize that the 'missing link' between serum ferritin and ischaemic heart disease in men is the relationship between serum ferritin, serum triglycerides and blood pressure.

This paper reviews current knowledge of childhood sarcoidosis with regard to the epidemiology in Danes, clinical presentation, diagnostic procedures, treatment and prognosis. Sarcoidosis is a granulomatous disease of unknown aetiology, with multiorgan involvement. The diagnosis is confirmed by the demonstration of epitheloid cell granulomas in tissue biopsy specimens. During the period 1980-92, three cases of childhood sarcoidosis were recorded in Copenhagen County, which has a total population of 610,000. The approximate incidence of clinically recognized sarcoidosis in Danish children younger than 15 y of age was 0.22-0.27/100,000 children per year, corresponding to approximately three new cases in Denmark each year. The true incidence is unknown, since the disease is often asymptomatic and resolves without a clinical diagnosis being made. In children younger than 5 y of age, the disease is characterized by involvement of skin, eyes and joints, whereas in older children involvement of lungs, lymph nodes and eyes predominate. The mainstay of treatment consists of oral corticosteroids. The risk/benefit ratio of using long-term corticosteroids needs to be evaluated in each individual patient. Some patients may benefit from additional therapy with methotrexate. The long-term prognosis is not well established, but it seems to be poorer in children younger than 5 y. Older children appear to have as favourable a prognosis as young adults.

Background & Aims: Helicobacter pylori infection was recently associated with iron-deficiency anemia. The aim of this study was to examine the relationship between H. pylori infection, hemoglobin, and iron status using serum ferritin as a marker for total body iron., Methods: Serum ferritin, hemoglobin, and immunoglobulin G (IgG) antibodies against H. pylori were assessed in 2794 Danish adults who attended a population survey. IgG antibodies were measured with an in-house enzyme-linked immunosorbent assay, serum ferritin with an immunoradiometric assay, and hemoglobin with Coulter-S., Results: The seroprevalence of H. pylori infection did not relate to hemoglobin. Serum ferritin levels were significantly lower in men (114 vs. 120 microg/L; P = 0.01) and in postmenopausal women (63 vs. 77 microg/L; P = 0.02) who were IgG positive than in seronegative individuals. IgG-positive people more often had reduced serum ferritin levels (

The aim of the present study was to evaluate the influence of menstruation, method of contraception, and iron supplementation on iron status in young Danish women, and to assess whether iron deficiency could be predicted from the pattern of menstruation. Iron status was examined by measuring serum (S-) ferritin and hemoglobin (Hb) in 268 randomly selected, healthy, menstruating, nonpregnant Danish women aged 18-30 years. Iron deficiency (S-ferritin <16 microg/l) was observed in 9.7%, of the women, iron deficiency anemia (S-ferritin < 13 microg/l and Hb < 121 g/l) in 2.2%. Iron supplementation, predominantly as vitamin-mineral tablets containing 14-20 mg of ferrous iron was used by 35.1%. The median serum ferritin was similar in non-iron users and in iron users, whereas the prevalence of iron deficiency was 12.6% in nonusers vs. 4.3% in users, the prevalence of iron deficiency anemia 3.4% in nonusers vs. 0%, in users (p=0.17) In non-iron-supplemented women, S-ferritin levels were inversely correlated with the duration of menstrual bleeding (rs= -0.25, p<0.001) and with the women's assessment of the intensity of menstrual bleeding (r(s)= -0.27, p<0.001), whereas no such correlations were found in iron-supplemented women. The results demonstrate that even moderate daily doses of ferrous iron can influence iron status in women with small iron stores. Women using hormonal contraceptives had menstrual bleeding of significantly shorter duration than those using intrauterine devices (IUD) or other methods. There was a high prevalence of small and absent body iron stores in young women, suggesting that preventive measures should be focused on those women whose menstruation lasts 5 days or longer, who have menstrual bleeding of strong intensity, who use an IUD without gestagen, and who are blood donors.