Leslie M. Klevay

Is the Western diet adequate in copper

Copper has been known to be essential for health for more than three quarters of a century. Myriad experiments with animals reveal that the cardiovascular, musculoskeletal and nervous systems are most sensitive to deficiency. Copper in the Western diet has been decreasing at least since the 1930s; half of the adult population consumes less than the amount recommended in the European Communities and the United Kingdom. At least one fourth of adults consume less than the estimated average requirement published for the United States and Canada. Hundreds of people have been reported in journals about medicine and neurology rather than nutrition to have impaired copper nutriture based on the criteria of low copper concentrations and low activities of enzymes dependent on copper in various fluids and tissues. In contrast, only 46 people have participated in depletion/repletion experiments needed to define requirements. Almost 1000 people have benefited from supplements containing copper in controlled trials. People deficient in copper are being identified increasingly; it is unknown if unusually high requirements or unusually low diets are causal. Alzheimers disease, ischemic heart disease and osteoporosis are the most likely human illnesses from low copper intakes.

Blood Pressure and Heat Shock Protein Expression in Response to Acute and Chronic Stress

We previously demonstrated that restraint and pharmacological agents that activate sympathetic nervous system activity induce expression of the 70-kD heat shock protein (HSP70) in major blood vessels. The magnitude and rapidity in which HSP70 is induced in the aorta suggest that it may play a salient role in the mechanical properties of vascular smooth muscle. Other investigators have reported that HSP70 inducibility is increased in genetically hypertensive animals. In this report, we have investigated the effects of acute and chronic (8-week) exposure to restraint and restraint in the presence of a randomized intermittent air jet on the development of hypertension and the induction of HSP70 in the aorta and adrenal glands of normotensive adult male Sprague-Dawley rats. Acute restraint or air jet resulted in a fivefold to sixfold increase in aortic HSP70 mRNA expression. Chronic exposure to restraint reduced the HSP70 response to acute restraint. In contrast, no adaptation of the HSP70 response to acute air jet was observed in aortas of chronically air jet-treated rats. In adrenal glands, HSP70 expression was reduced after chronic restraint and air jet, indicating that in this tissue, adaptation occurs to both stressors. There was no difference in HSP70 expression in unstressed rats that had been chronically exposed to restraint or air jet in either adrenal gland or aorta. A significant increase (P < .05) in systolic blood pressure developed in air jet-treated animals (120 +/- 3 mm Hg) but not in restrained rats (107 +/- 2 mm Hg) compared with unstressed controls (106 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

IHD from copper deficiency: a unified theory.

The theory, in brief outline here, implicating deficiency of Cu in the aetiology and pathophysiology of IHD explains more attributes of the disease than any other theory. This theory satisfies several of Hills criteria of a half-century ago for deducing association between an environmental feature and presence of an illness. Most important is the temporal association between the rise of IHD and the decrease in dietary Cu since the 1930s along with a parallel increase in the supplementation of pregnant women with Fe, a Cu antagonist. There are more than eighty anatomical, chemical and physiological similarities between animals deficient in Cu and individuals with IHD. Few of these similarities have been produced by other dietary manipulations because feeding cholesterol induces Cu deficiency in animals. The most recent of these to be identified is decreased serum dehydroepiandrosterone. Some concomitant aspects of Cu metabolism and utilisation have been identified in other theories about heart disease: fetal programming, homocysteine, and Fe overload.

Bariatric Surgery and the Assessment of Copper and Zinc Nutriture

In a recent issue of Obesity Surgery, Ernst et al. [1] admonish us to assess nutriture of candidates for bariatric surgery pre-operatively because they found considerable malnutrition in the morbidly obese. Albumin, vitamin D, and zinc deficiencies were emphasized, although other metabolic abnormalities were identified. The prevalence of zinc deficiency may have been overestimated and that of copper, underestimated. Obese people experience chronic inflammation resembling that found in infectious disease [2, 3]. Although it is not certain that quality and quantity of inflammation are identical in infection and obesity, it seems likely that zinc and copper metabolism are altered similarly by cytokines [4] and signaling pathways [2] in both conditions. Pepys [4] describes the acute-phase response to acute and chronic inflammation: a number of plasma proteins, such as ceruloplasmin, are synthesized in liver under the influence of cytokines and are secreted into the circulation. A few other proteins, such as albumin, show a concomitant decrease. Some of the decline albumin observed by Ernst et al. [1] may have resulted from inflammation. Albumin is the principal zinc-binding protein [5] in serum. With lower albumin, there are fewer binding sites for zinc. Because some of the decrease in zinc observed by Ernst et al. [1] may have been from cytokine effects on albumin, zinc deficiency may have been less than 25%. Perhaps the estimate of zinc deficiency can be improved by assessing nutriture with measurements of zinc in erythrocytes and hair or by measuring activities of enzymes dependent on zinc [5]. No low values for serum copper were found in a sub-sample of the population described by Ernst et al. [1]. If copper deficiency was present, diagnosis may have been masked by cytokine effects that increased serum copper values because ceruloplasmin is the predominant carrier of circulating copper [6]. Perhaps copper deficiency would have been found if patients had been evaluated with some of the newer, potentially more sensitive, indices of copper status such as erythrocyte and extracellular superoxide dismutases, leukocyte copper, platelet cytochrome c oxidase or serum lysyl oxidase [7–11] Although the Western diet often is low in copper [12, 13], copper deficiency has not been reported in patients before bariatric surgery. Deficiency is being noticed increasingly after surgery, however [14–16]. Ernst et al. [1] suggest that micronutrient deficiencies contribute to the well-known health impairing effects of obesity and note, according to Sjöström and Adams et al. [17, 18], that bariatric surgery produces highly significant improvement in mortality from heart disease, diabetes mellitus and cancer, etc. However, Adams et al. [18] also found an increase in deaths, post-surgery, from accidents and suicide. As a wide variety of disabling neurological complications are associated with bariatric surgery [19], perhaps neurological diseases of nutritional origin contributed to the L. M. Klevay (*) Department of Internal Medicine, University of North Dakota School of Medicine and Health Sciences, 223 27th Avenue South, Grand Forks, ND 58201, USA e-mail: leslie.klevay@und.edu

Myelin and traumatic brain injury: The copper deficiency hypothesis

Nearly two million people suffer traumatic brain injury in the US each year. These injuries alter adversely the metabolism of myelin, a major lipid material in brain, both in people and in experimental injuries of animals. A newly discovered and severe human neuropathy from copper deficiency provides evidence that some people in the US are malnourished in copper. As it is well known among copper cognoscenti that it is impossible to synthesize myelin if copper nutriture is inadequate, it seems reasonable to assume that repair will be poor in this situation. Copper status of patients should be evaluated and experiments with injured animals should be repeated with graded doses of copper to determine if copper metabolism is important in this illness.

Copper and cognition

Kayser and Tenke (this issue) provide a nice history and editorial review of the critical EEG reference electrode issue and critique of REST, the reference electrode standardization technique, apparently first implemented by Yao (Yao, 2001; Yao et al., 2005; Qin et al., this issue). For many years, EEG scientists seemed to insist (based on both word and deed) that if only some body location could be found with no active local sources, such reference location would allow for genuine reference-free recordings. This old idea has long been discredited in many publications using both simulations and genuine data (Rush and Driscoll, 1969; Nunez, 1981; Nunez and Srinivasan, 2006; Yao et al., 2007). I will refer here to the reference-free potential or nominal potential with respect to infinity. The label ‘‘nominal” reminds us that even if it Clinical Neurophysiology 121 (2010) 2177–2183

Zinc Absorption Adapts to Zinc Supplementation in Postmenopausal Women

Objective: To determine if human Zn absorption adapts to chronic high Zn intakes. Methods: Zn absorption was measured at 0, 8, and 16 wk in healthy postmenopausal women who consumed controlled diets with ∼5 mg Zn from food, supplemented to 14 (n = 6), 32 (n = 3), or 47 (n = 3) mg Zn/d for 22 wk. Zn absorption for 1 day was determined by 65Zn-labeling of meals and whole body scintillation counting. Results: At wk 0, less Zn was absorbed from diets with 14, compared with 32 or 47 mg/d (4.6, 8.7, and 10.3 mg/d, respectively; pooled SE = 0.9; p < 0.05). These differences were not apparent at wk 8 (5.4, 5.8, 6.4; NS) and became negligible by wk 16 (5.0, 5.0, 5.1; NS). Plasma Zn concentrations were unaffected. The results are consistent with a saturation response model of Zn absorption. Conclusion: Within several weeks, postmenopausal women biologically adapted to absorb a relatively uniform amount of 5 mg Zn/d when controlled, Zn-supplemented diets supplied consistent Zn intakes between 14 and 47 mg/d.

Copper and public health: Dietary intakes vs. clinical data

Nakatsuka et al. [1] measured mineral elements in food samples epresenting daily food intakes of nearly 300 children in northeastrn Japan to evaluate the accuracy of intakes calculated from food omposition tables. Significant differences were detected for all ine minerals suggesting that care should be taken when calculatng mineral intakes. Calculated intakes of copper, iron, magnesium nd sodium were too high by approximately 20%. Their data on copper help to unearth an important problem in he use of dietary histories and food tables in the estimation of ntakes. To date, nine other publications with comparisons similar o those of the authors have been found (for references see [2]). ine of the ten showed that calculated copper was greater than easured copper (probability by sign test = 0.0098) [3]. Thus there s a systematic, or determinate, error in the estimation of copper ntakes by calculation giving results that are falsely high. The authors help to extend this concept to non-Western diets nd confirm the findings of Chiplonkar et al. [4]. Together, the averge, calculated excess copper for Asian diets is 11%, and is less than he average for eight Western diets, 77%. The source of the copper error(s) must be identified because ystematic overestimation of copper intakes of individuals and opulations provides a false sense of security. In contrast is the ollection [2] of more than 60 medical publications on 2500 peole with impaired copper status based on the criteria of the Oxford extbook of Medicine [5] of low copper concentrations or low activties of enzymes depending on copper. Whether or not the errors n the other minerals evaluated by the authors are important in valuating public health is unknown.

Letter to the Editor: regarding “Copper deficiency and neuropathology related to the petrous bone”

Mendy et al. [1] found that low bone mineral density was associated with poor balance and hearing impairment among nearly 9000 subjects of the National Health and Nutrition Examination Survey (2004). They define osteoporosis as reduced bone mineral density and hypothesize that the neurologic deficits are the results of alterations in the petrous part of the temporal bone. Abnormal copper metabolism may be implicated in this triad because copper deficiency is the only environmental insult known to affect balance, bone density, and hearing. A new and severe neuropathy [2] is being found increasingly now and in the last decade. It resembles that of pernicious anemia, but it responds to copper rather than vitamin B12. Poor balance is the most common presenting complaint [3] and probably is from cerebellar injury [4,5]. Absent reflexes, unsteady gait, difficulty in writing, and absent taste [6] also occur. The neuropathy seems rare enough to be published, but common enough that 10e15 cases can be reported from single clinics [7,8]. It may as common as that of vitamin B12 deficiency and may be the most important alternative in differential diagnosis of the latter [3]. Diets low in copper may be contributory because copper in the Western diet has been decreasing at least since the 1930s, and substantial numbers of adults consume less than the estimated average requirement published for the United States and Canada [9]. The authors [1] found that impairment of hearing or of balance increased with increasing frequency of vitamin B12 deficiency, confusion, memory problems, and visual impairments. These signs were rather frequent among their subjects and can be caused by vitamin B12 deficiency [3]. Deficiencies of copper and vitamin B12 can coexist [3]. Visual disturbances have been reported in human copper deficiency. There can be no medical doubt that copper deficiency can cause osteoporosis in people [10] because copper deficient people have osteoporosis that can be cured with extra copper (for references see [11]). Two double-blind placebo-controlled trials have shown that trace element supplements including copper improve bone mineral density in postmenopausal women [10]. A half-dozen medical publications contain data on low copper status in some 400 people with fractures and low bone mineral density (for references see [9]). Copper metabolism probably is important in the author’s [1] findings. A decrease in auditory startle response, probably from poor hearing, occurred in rats with perinatal copper deficiency [12]. A strain of mice (C57) with hearing loss early in life also has early hair cell loss and decreased activity of superoxide dismutase in the

Intakes of copper in nutrition surveys are falsely high

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