Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study.

BACKGROUND: Iron-loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first-degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH. OBJECTIVE: To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs. DESIGN: Population-based cohort study. SETTING AND SUBJECTS: A total of 3531 haemochromatosis patients and 11 794 FDRs were identified using nationwide, population-based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997-2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression. RESULTS: Of the 3531 patients, 259 were diagnosed with IHD compared with 3077 of the 37 369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03-1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15-4.81). Of 11 794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6197 among FDRs of controls (HR = 1.05; 95% CI, 0.97-1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72-1.56). CONCLUSIONS: In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD.

Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis.

AIM: Duodenal adenomatosis in familial adenomatous polyposis results in a cancer risk that increases with age. Endoscopic surveillance has been recommended, but the effect has not yet been documented. The aim of this study was to present the results of long-term duodenal surveillance and to evaluate the risk of cancer development. METHOD: Follow up of patients in a previous study with gastroduodenoscopy in 1990-2010. Statistical analysis included the χ(2) test, actuarial method and Kaplan-Meier analysis. RESULTS: Among 304 patients, 261 (86%) had more than one endoscopy. The median follow up was 14 (interquartile range, 9-17) years. The cumulative lifetime risk of duodenal adenomatosis was 88% (95% CI, 84-93), and of Spigelman stage IV was 35% (95% CI, 25-45). The Spigelman stage improved in 32 (12%) patients, remained unchanged in 88 (34%) and worsened in 116 (44%). Twenty (7%) patients had duodenal cancer at a median age of 56 (range, 44-82) years. The cumulative cancer incidence was 18% at 75 years of age (95% CI, 8-28) and increased with increasing Spigelman stage at the index endoscopy to 33% in Spigelman stage IV (P < 0.0001). The median overall survival was 6.4 years (95% CI, 1.7 to not estimated): 8 years after a screen-detected cancer vs 0.8 years (95% CI, 0.03-1.7) after a symptomatic cancer (P < 0.0001). The location of the mutation in the APC gene did not influence the risk of developing Spigelman stage IV (P = 0.46) or duodenal cancer (P = 0.83). CONCLUSION: The risk of duodenal cancer in familial adenomatous polyposis is considerable, and regular surveillance and cancer prophylactic surgery result in a significantly improved prognosis.

Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.

BACKGROUND: The majority of hemochromatosis patients are homozygous for the HFE-C282Y mutation. However, less than half of C282Y homozygous subjects identified by population screening studies actually develop the disease. The cytokine TNF-alpha is implicated in the regulation of iron metabolism at different levels. Our aim was to study the role of TNF-alpha and its promoter polymorphisms in the phenotypic expression of hemochromatosis in individuals with and without the C282Y mutation. METHODS: We studied 4 groups of 10 subjects each: (1) C282Y homozygotes without clinical hemochromatosis; (2) C282Y homozygotes with hemochromatosis; (3) secondary hemochromatosis (without C282Y mutation); and (4) controls. Groups were age-matched and sex-matched. Peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) and the release of TNF-alpha was measured. Additionally, the G/A polymorphisms at position -238 and -308 of the TNF-alpha, gene were determined by PCR and RFLP analysis in 178 hemochromatosis patients and 41 controls. RESULTS: TNF-alpha production from PBMC at 8 and 24 h after increasing concentrations of LPS stimulation were similar in the four groups. The prevalence of TNF-alpha polymorphisms was similar in patients and controls. The prevalences of cirrhosis, siderosis, median s-ferritin and median ALT values were similar in patients with and without the TNF-alpha polymorphisms. CONCLUSIONS: Neither TNF-alpha, released from PBMC nor the presence of TNF-alpha polymorphisms seem to be associated with disease manifestation in hemochromatosis.