Disease-Related Conditions in Relatives of Patients with Hemochromatosis

Bulaj, Zaneta J.; Ajioka, Richard S.; Phillips, John D.; LaSalle, Bernie; Jorde, Lynn B.; Griffen, Linda M.; Edwards, Corwin Q.; Kushner, James P.

doi:10.1056/nejm200011233432104

Cited by 196 publications

(135 citation statements)

References 18 publications

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“…This is consistent with the large degree of phenotypic variation in terms of other morbidities in subjects with haemochromatosis that has been attributed at least in part to other genetic modifiers [22,35]. Our studies of mouse models of the disease demonstrate that iron overload may actually be protective of diet-induced obesity (unpublished results), and the same mechanisms may be operative in humans.…”

Section: Discussionsupporting

confidence: 85%

“…A subgroup of the above were individuals who were not themselves referred because of haemochromatosis but who were found to have haemochromatosis in the course of family screening or screening at blood donation [22]. This clinically unselected group included 46 in the age range 50-79 years, and six (13%, 95% CI 6-26) had diabetes by self-report.…”

Section: Historical Review Of Diabetes Prevalence Data In Haemochromamentioning

confidence: 99%

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High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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Aims/hypothesis: The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects and methods: Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. Results: The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Conclusions/interpretation: Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

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Section: Discussionsupporting

confidence: 85%

Section: Historical Review Of Diabetes Prevalence Data In Haemochromamentioning

confidence: 99%

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

et al. 2006

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“…17 -23 If restricted to the full clinical picture of haemochromatosis, the penetrance may be as low as less than 1 24 or 2% 25 . If haemochromatosis is defined as iron accumulation in conjunction with clinical findings that were consistent with haemochromatosis, the penetrance was as high as 50 26 to 52% 27 . These different figures reflect the variable expression of a common disease, which, for presently unknown reasons, is rarely seen in its full clinical expression.…”

Section: Discussionmentioning

confidence: 99%

Genotype-based screening for hereditary haemochromatosis. I: Technical performance, costs and clinical relevance of a German pilot study

2004

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In 2001, we initiated a pilot study on DNA-based screening of hereditary haemochromatosis (HH) in Germany. A total of 5882 insurants of the German sickness fund Kaufmännische Krankenkasse -KKH requested information on this project, and 3961 of these individuals provided blood samples for testing of the HFE mutation C282Y. Of these, 3930 samples were successfully tested with two independent test methods, and the results were communicated to the referring doctors. In all, 67 of the tested individuals were homozygous for C282Y. Partially, this high rate (1.7%) can be explained by the fact that 42.6% of the homozygotes already knew their clinical diagnosis HH before sending the blood sample. Iron accumulation with further signs or symptoms of HH was present in eight of 34 newly diagnosed C282Y homozygous individuals. Two major aspects of our study were the analytic validity and the direct laboratory costs of different test methods. Of 7860 tests performed, 7841 (99.6%) gave correct results. The overall error rate was 0.24% (95% CI: 0.15 -0.38%). The analytic specificity of the tests methods with respect to the detection of homozygosity for C282Y was 100% (7726 of 7726 nonhomozygous test challenges, 95% CI: 99.95-100%), while the analytic sensitivity was 97% (130 of 134 homozygous test challenges, 95% CI: 92.5-99.2%). The direct costs ranged from 11.20 -16.35 h per test method. We conclude that the test methods for C282Y are robust, highly sensitive and specific, and that a DNA-based HH-screening program can be performed at reasonable laboratory costs.

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“…However, the severity of the disease varies greatly. It is well established that the majority of homozygotes will have increased transferrin saturation and serum ferritin (SF) (3,(12)(13)(14)(15)(16) , but the percentage of homozygotes who will develop clinical symptoms is still unclear. Factors influencing the progress of the disease remain poorly understood.…”

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confidence: 99%

The effect of dietary iron intake on the development of iron overload among homozygotes for haemochromatosis

Tao

Pelletier

2009

Public Health Nutr.

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Objective: To quantify the role of dietary Fe in total body Fe (TBI) accumulation among homozygotes for the HFE gene associated with haemochromatosis. Design: A Monte Carlo model was built to simulate Fe accumulation based on findings from human feeding experiments and national dietary surveys. A hypothetical cohort of 1000 homozygotes with starting age 25 years was used in 39-year simulations. The impact of reducing dietary Fe intake on Fe accumulation was tested. Results: In the baseline model without any dietary intervention, by age 64, the percentage of males with TBI . 10 g, .15 g and .20 g was 93?2 %, 49?6 % and 14?7 %, respectively. When the Fe intake of individuals in the cohort was reduced to #200 % of the recommended dietary allowance (RDA), the corresponding percentages were 92?0 %, 40?5 % and 10?2 %, respectively. The corresponding figures were 91?0 %, 40?0 % and 9?3 % for Fe defortification and 70?3 %, 21?3 % and 4?1 % when Fe intake was capped at 100 % RDA. Similar trends were seen with sexes combined, although the impact of interventions was less. Sensitivity analysis revealed that the rate of Fe accumulation and the impact of dietary interventions are highly dependent on assumptions concerning Fe absorption rates. Conclusions: Variation in Fe intake as currently observed in the USA contributes to variation in Fe accumulation among homozygotes, when continued over an extended period. Lifelong dietary habits and national fortification policy can affect the rate of Fe accumulation, although the magnitude of the effect varies by gender, the TBI level of interest and factors affecting the Fe absorption rate.

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Disease-Related Conditions in Relatives of Patients with Hemochromatosis

Abstract: A substantial number of homozygous relatives of patients with hemochromatosis--more commonly men than women--have conditions related to hemochromatosis that have yet to be detected clinically.

Cited by 196 publications

References 18 publications

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

Genotype-based screening for hereditary haemochromatosis. I: Technical performance, costs and clinical relevance of a German pilot study

The effect of dietary iron intake on the development of iron overload among homozygotes for haemochromatosis

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