Copper deficiency may be a leading cause of ischaemic heart disease

DiNicolantonio, James J.; Mangan, D F; O’Keefe, James H.

doi:10.1136/openhrt-2018-000784

Cited by 100 publications

(68 citation statements)

References 91 publications

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“…It has been shown that iron deficiency upregulates lipogenic genes but downregulates apolipoprotein H and genes involved in the mitochondrial beta-oxidation, resulting in increased circulating lipids [ 48 ]. For copper, its deficiency has long been linked to increased risks of hyperlipidemia and cardiovascular diseases in both humans and animal models [ 49 ], while copper supplementation in patients of hyperlipidemia was shown to improve the blood lipid profile [ 50 ]. Multiple possible molecular mechanisms have been suggested for the effect of copper deficiency on lipid metabolism disorders, mainly from studies on copper-deficient rats.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple possible molecular mechanisms have been suggested for the effect of copper deficiency on lipid metabolism disorders, mainly from studies on copper-deficient rats. First, copper deficiency has been shown to increase the level of a key enzyme in the cholesterol synthesis pathway, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase [ 49 , 51 ]. An intestinal transcriptome analysis found that in copper-deficient rats, genes involved in mitochondrial and peroxisomal fatty acids beta-oxidation are down-regulated, and genes involved in plasma cholesterol transport are up-regulated [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

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The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

et al. 2020

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Blood levels of iron and copper, even within their normal ranges, have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. This study aims to examine the causal clinical effects of blood iron and copper with Mendelian randomization (MR) analyses. Genetic instruments for the blood levels of iron and copper were curated from existing genome-wide association studies. Candidate clinical outcomes were identified based on a phenome-wide association study (PheWAS) between these genetic instruments and a wide range of phenotypes in 310,999 unrelated individuals of European ancestry from the UK Biobank. All signals passing stringent correction for multiple testing were followed by MR analyses, with replication in independent data sources where possible. We found that genetically predicted higher blood levels of iron and copper are both associated with lower risks of iron deficiency anemia (odds ratio (OR) = 0.75, 95% confidence interval (CI): 0.67–0.85, p = 1.90 × 10−6 for iron; OR = 0.88, 95% CI: 0.78–0.98, p = 0.032 for copper), lipid metabolism disorders, and its two subcategories, hyperlipidemia (OR = 0.90, 95% CI: 0.85–0.96, p = 6.44 × 10−4; OR = 0.92, 95% CI: 0.87–0.98, p = 5.51 × 10−3) and hypercholesterolemia (OR = 0.90, 95% CI: 0.84–0.95, p = 5.34 × 10−4; OR = 0.93, 95% CI: 0.89–0.99, p = 0.022). Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. Multiple sensitivity tests were applied to assess the presence of pleiotropy and the robustness of causal estimates. Regardless of the approaches, consistent evidence was obtained. Moreover, the unique clinical effects of each blood mineral were identified. Notably, genetically predicated higher blood iron is associated with an enhanced risk of varicose veins (OR = 1.28, 95% CI: 1.15–1.42, p = 4.34 × 10−6), while blood copper is positively associated with the risk of osteoarthrosis (OR = 1.07, 95% CI: 1.02–1.13, p = 0.010). Sex-stratified MR analysis further revealed some degree of sex differences in their clinical effects. Our comparative PheWAS-MR study of iron and copper comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in hyperlipidemia and hypercholesterolemia. Given the modifiable nature of blood mineral status and the potential for clinical intervention, these findings warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

et al. 2020

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“…Various myelopathies and peripheral neuropathies have been reported with copper deficiency, some of which were severe and irreversible [3,4,18,19]. In addition, although copper deficiency has been observed as a possible cause of ischemic heart disease by significantly promoting major risk factors such as hypercholesterolemia, chronic inflammation, oxidative stress, and glucose intolerance [20], our patient had normal cholesterol and lipid profiles.…”

Section: Discussionmentioning

confidence: 65%

First Case Report of Acquired Copper Deficiency Following Revisional Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S) Leading to Severe Pancytopenia with Refractory Anemia

Abusabeib

Ansari

2020

OBES SURG

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“…Recent data suggest that insufficient dietary intake is a widespread issue . The link between cardiovascular disease and copper was first discovered in animals and confirmed in humans in the 1990s .…”

Section: Causesmentioning

confidence: 99%

“…It was only recently shown that other clinically relevant deficiencies were potentially present in different medical conditions such as burns, bariatric surgery, or other malabsorption syndromes. Until recently, copper deficiency was considered as uncommon; however, the number of case reports, investigations in the area of cardiovascular diseases and fat metabolism, and animal studies have suggested that copper deficiency might actually represent a public health issue …”

Section: Introductionmentioning

confidence: 99%

Copper Deficiency: Causes, Manifestations, and Treatment

et al. 2019

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Background: The metabolism of the essential trace element copper remains incompletely understood and, until recently, nearly ignored in acute medicine. Menkes disease was for long the only known copper deficiency condition, but several case reports and investigations conducted over the last 2 decades have shown that deficiency is more frequent than previously suspected, with devastating individual consequences and potential public health consequences. The copper needs in healthy individuals are 0.9 mg/d, which translates to 0.3 mg/d intravenously in parenteral nutrition; the present review aims at gathering actual knowledge. Method and results: A review of literature was conducted in PubMed and Cochrane systematic reviews to identify the most recent information about copper deficiency and generate a narrative review. Copper deficiency has hereditary and acquired origins, the latter being the most frequent. Clinical manifestations are nonspecific but affect all organs and systems, particularly the hematologic (anemia) and the neurologic (myeloneuropathy) systems. Deficiency also affects the cardiovascular, cutaneous, and immune systems. Severe copper deficiency due to reduced absorption after bariatric bypass surgery has become frequent. Conclusion: Deficiency is more frequent than previously recognized, probably because of changing nutrition patterns but also because of some treatments that have become very common such as bypass bariatric surgery and, in acute medicine, prolonged continuous renal replacement therapy. The patients may present with severe hematologic and neurologic complications that go untreated because copper deficiency was not considered in the differential diagnosis: These complications often need active intravenous repletion with doses 4-8 times the usual nutrition recommendations. (Nutr Clin Pract. 2019;34:504-513)

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Copper deficiency may be a leading cause of ischaemic heart disease

Cited by 100 publications

References 91 publications

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

First Case Report of Acquired Copper Deficiency Following Revisional Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S) Leading to Severe Pancytopenia with Refractory Anemia

Copper Deficiency: Causes, Manifestations, and Treatment

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