Discovery and importance of zinc in human nutrition

The present explosion in knowledge of zinc has been the result of several factors, the major ones being the recognition of the important role of zinc in human health and diseases, its vital functions in biochemical reactions, and the technological advances that make it feasible to quantitate this essential trace element in biological fluids. Deficiency of zinc in humans due to nutritional factors and several disease states has now been recognized. The high phytate content of cereal proteins is known to decrease the availability of zinc; thus, the prevalence of zinc deficiency is likely to be high in a population consuming large quantities of proteins. Alcoholism, malabsorption, sickle cell anemia, chronic renal disease, and chronically debilitating diseases are now known to be predisposing factors for zinc deficiency. A severe deficiency of zinc such as that seen in patients with acrodermatitis enteropathica may be life-threatening. A spectrum of clinical manifestations ranging from mild to severe degrees has now been recognized in human zinc deficiency states. Zinc appears to be involved in many biological functions including DNA synthesis. Roles for zinc in enzymatic functions, cell membranes, and immunity are now well established.     

Zinc against COVID-19? Symptom surveillance and deficiency risk groups

A wide variety of symptoms is associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and these symptoms can overlap with other conditions and diseases. Knowing the distribution of symptoms across diseases and individuals can support clinical actions on timelines shorter than those for drug and vaccine development. Here, we focus on zinc deficiency symptoms, symptom overlap with other conditions, as well as zinc effects on immune health and mechanistic zinc deficiency risk groups. There are well-studied beneficial effects of zinc on the immune system including a decreased susceptibility to and improved clinical outcomes for infectious pathogens including multiple viruses. Zinc is also an anti-inflammatory and anti-oxidative stress agent, relevant to some severe Coronavirus Disease 2019 (COVID-19) symptoms. Unfortunately, zinc deficiency is common worldwide and not exclusive to the developing world. Lifestyle choices and preexisting conditions alone can result in zinc deficiency, and we compile zinc risk groups based on a review of the literature. It is also important to distinguish chronic zinc deficiency from deficiency acquired upon viral infection and immune response and their different supplementation strategies. Zinc is being considered as prophylactic or adjunct therapy for COVID-19, with 12 clinical trials underway, highlighting the relevance of this trace element for global pandemics. Using the example of zinc, we show that there is a critical need for a deeper understanding of essential trace elements in human health, and the resulting deficiency symptoms and their overlap with other conditions. This knowledge will directly support human immune health for decreasing susceptibility, shortening illness duration, and preventing progression to severe cases in the current and future pandemics.     

Domestic animals in the elucidation of zinc's role in nutrition

Parakeratosis in swine, a disease that caused severe economic losses in many commercial herds during the late 1940's and early 1950's, was caused by an inadequate intake of zinc. In addition to poor growth, the disease involves primarily the epidermal layer of the skin, which in severe cases becomes thickened and heavily encrusted. Finally, deep fissures develop in the encrusted areas. The low availability of zinc in plant protein sources and the increasing use of soybean meal in practical-type diets during the late 1940's contributed to the increasing incidence of the disease. Excessive levels of calcium also increased the incidence and severity of the disease. Prominent features of zinc deficiency in poultry were failure of normal development of long bones and the occurrence of severe lesions on the feet and legs. As with the pig, the low bioavailability of zinc from plant protein sources led to the observation that practical-type diets were limiting in this metal. Although parakeratosis can be produced in cattle fed diets low in zinc, it does not seem to have been a major nutritional problem in ruminants.     

Zinc Supplementation or Regulation of its Homeostasis: Advantages and Threats

To accomplish its multifunctional biological roles, zinc requires precise homeostatic mechanisms. There are efficient mechanisms that regulate zinc absorption from the alimentary tract and its excretion by the kidney depending on the organism demands. The regulatory mechanisms of cellular zinc inflow, distribution, and zinc outflow are so efficient that symptoms of zinc deficiency are rare, and symptoms connected with its massive accumulation are even more rare. The efficiency of homeostatic mechanisms that prevent zinc deficiency or excessive zinc accumulation in the organism is genetically conditioned. It seems that an essential element of zinc homeostasis is the efficiency of zinc transmembrane exchange mechanisms. Intracellular free zinc concentration is higher than in extracellular space. Physiologically, the active outflow of zinc ions from the cell depends on the increase of its concentration in extracellular space. The ion pumps activity depends on the efficiency by which the cell manages energy. Considering the fact that zinc deficiency accelerates apoptosis and that excessive zinc accumulation inside cells results in a toxic effect that forces its death brings about several questions: Is intensification and acceleration of changes in zinc metabolism with age meaningful? Is there a real zinc deficiency occurring with age or in connection with the aforementioned pathological processes, or is it just a case of tissue and cell redistribution? When discussing factors that influence zinc homeostasis, can we consider zinc supplementation or regulation of zinc balance in the area of its redistribution? To clarify these aspects, an essential element will also be the clear understanding of the nomenclature used to describe changes in zinc balance. Zinc homeostasis can be different in different age groups and depends on sex, thus zinc dyshomeostasisrefers to changes in its metabolism that deviate from the normal rates for a particular age group and sex. This concept is very ample and implies that zinc deficiency may result from a low-zinc diet, poor absorption, excessive loss of zinc, zinc redistribution in intra- and extracellular compartments, or a combination of these factors that is inadequate for the given age and sex group. Such factor or factors need to be considered for preventing particular homeostasis disorders (or dyshomeostasis). Regulation of zinc metabolism by influencing reversal of redistribution processes ought to be the main point of pharmacologic and nonpharmacologic actions to reestablish zinc homeostasis. Supplementation and chelation are of marginal importance and can be used to correct long-term dietary zinc deficiency or zinc poisoning or in some cases in therapeutic interventions. In view of its biological importance, the problem posed by the influence of zinc metabolism requires further investigation. To date, one cannot consider, for example, routine zinc supplementation in old age, because changes of metabolism with age are not necessarily a cause of zinc deficiency. Supplementation is warranted only in cases in which deficiency has been established unambiguously. An essential element is to prevent sudden changes in zinc metabolism, which lead to dyshomeostasis in the terms defined here. The primary prophylaxes, regular physical activity, efficient treatment of chronic diseases, are all elements of such prevention.     

Zinc status in human immunodeficiency virus infection

Plasma zinc and copper concentrations, erythrocyte zinc concentration, copper-zinc superoxide dismutase activity and urinary zinc concentrations were determined for control subjects and individuals with AIDS, ARC, or asymptomatic HIV infection. Significant differences among the population groups were not noted for the above parameters with the exception of plasma copper which was higher in the AIDS group than in other patient groups. These results do not support the idea that zinc deficiency is a common contributory factor of HIV infectivity or clinical expression, nor that HIV infection induces a zinc deficiency.     

Estimating the Global Prevalence of Zinc Deficiency: Results Based on Zinc Availability in National Food Supplies and the Prevalence of Stunting

Background

Adequate zinc nutrition is essential for adequate growth, immunocompetence and neurobehavioral development, but limited information on population zinc status hinders the expansion of interventions to control zinc deficiency. The present analyses were conducted to: (1) estimate the country-specific prevalence of inadequate zinc intake; and (2) investigate relationships between country-specific estimated prevalence of dietary zinc inadequacy and dietary patterns and stunting prevalence.

Methodology and Principal Findings

National food balance sheet data were obtained from the Food and Agriculture Organization of the United Nations. Country-specific estimated prevalence of inadequate zinc intake were calculated based on the estimated absorbable zinc content of the national food supply, International Zinc Nutrition Consultative Group estimated physiological requirements for absorbed zinc, and demographic data obtained from United Nations estimates. Stunting data were obtained from a recent systematic analysis based on World Health Organization growth standards. An estimated 17.3% of the world’s population is at risk of inadequate zinc intake. Country-specific estimated prevalence of inadequate zinc intake was negatively correlated with the total energy and zinc contents of the national food supply and the percent of zinc obtained from animal source foods, and positively correlated with the phytate: zinc molar ratio of the food supply. The estimated prevalence of inadequate zinc intake was correlated with the prevalence of stunting (low height-for-age) in children under five years of age (r = 0.48, P<0.001).

Conclusions and Significance

These results, which indicate that inadequate dietary zinc intake may be fairly common, particularly in Sub-Saharan Africa and South Asia, allow inter-country comparisons regarding the relative likelihood of zinc deficiency as a public health problem. Data from these analyses should be used to determine the need for direct biochemical and dietary assessments of population zinc status, as part of nationally representative nutritional surveys targeting countries estimated to be at high risk.     

Hypophosphatemia

Hypophosphatemia is a common laboratory abnormality that occurs in a wide variety of disorders. When severe and prolonged, it may be associated with rhabdomyolysis, brain dysfunction, myocardial failure and certain defects of erythrocyte function and structure. Other disorders ascribed to hypophosphatemia, including platelet dysfunction and thrombocytopenia, liver dysfunction, renal tubular defects, peripheral neuropathy, metabolic acidosis and leukocyte dysfunction are less well documented. In quantitative terms, the most severe phosphate deficiency is seen in patients who consume a phosphate-deficient diet in conjunction with large amounts of phosphate-binding antacids, in persons with severe, chronic alcoholism and in patients with wasting illnesses who are refed with substances containing an inadequate amount of phosphate. When severe hypophosphatemia occurs in such a setting, the clinical effects appear to be much more pronounced. While there have been some advances in our understanding of the pathophysiology of phosphate depletion and hypophosphatemia, much remains to be learned. Treatment of hypophosphatemia is controversial; however, there is little question that it is indicated in alcoholic patients and those with severe phosphate deficiency.     

Clinical examination of weanling rats with early zinc deficiency

In order to gain experience about the detection of adverse effects during a scientific procedure, we carried out a clinical examination of rats with zinc deficiency. In weanling rats fed a zinc-deficient diet (30 mumol zinc/kg) for 10 days, the mean tibial concentration of zinc was reduced by 53% and body weight gain by 73% when compared with rats fed a diet containing an adequate amount of zinc (150 mumol zinc/kg). In a small open field on day 9 of the experiment, the deficient rats more frequently displayed the posture standing upright with elevated heels. On day 10 of the experiment a clinical examination was carried out at random and 'blind' by three independent assessors. Out of 20 variables scored quantitatively on each individual animal, only body size differed between normal and deficient rats. Other classical signs of zinc deficiency, such as alopecia, dermatitis and diarrhoea, were not detected. It is concluded that in this rat model of zinc deficiency, no evidence for extreme discomfort can be demonstrated.     

Malformations, anomalies and variations in patients with severe iron deficiency]

In severe iron deficiency which frequently occurs in the population of Turkey, malformations, anomalies and variations are often observed. In 190 patients with severe iron deficiency of long duration such abnormalities could be found in 107 cases. The abnormal changes were of different character and occured in various parts of the body. In the majority multiple changes, ranging from 2 to 7 and more could be registered. 100 persons showing no iron deficiency and no anemia presented a much lower incidence of the same changes; in a second group of 54 patients suffering from a severe anemia without iron deficiency the incidence was still lower. These observations suggest that the occurrence of the abnormalities is closely connected with the iron deficiency. The character of the abnormal changes which are not susceptible to iron treatment are pointing to a prenatal origin. The diversity of the changes, the occurrence in various parts of the body and skeleton as well as the multiplicity of incidence are showing that they are due to impairment of the process of development in the embryonic organism. This view is supported by the results of the examination of the chromosomes. A distinct relation could be established between the incidence of the malformations and the occurrence of the chromosomal aberrations. As the iron deficiency in the Turkish population is mainly caused by an insufficient supply of iron with the food it is likely that by sufficient iron supply in pregnant women the incidence of malformations and anomalies caused by the iron deficiency can be prevented and by a general amelioration of the nutrition their occurrence in the population markedly reduced.     

Use of laboratory animals to define physiological functions and bioavailability of zinc

For the past 50 years laboratory animals have been used to ascertain the metabolic bases for signs of zinc deficiency such as sharply reduced food intake, severe dermatitis, slow wound healing, delayed sexual development and function, reduced immunocompetence, severe teratogenic abnormalities, and abnormal metabolism of carbohydrate, lipid, and protein. Current evidence indicates that many of these symptoms may be consequences of inhibition of early steps in nucleic acid metabolism that lead to problems with cellular replication and growth and also that zinc plays an important role in membrane structure and function. Bioavailability of zinc to experimental animals was early shown to be reduced by plant protein diets and to be further reduced by feeding excess calcium. Current evidence indicates phytic acid in plant proteins to be a major inhibitor of zinc absorption, although food-processing methods can either increase or decrease zinc bioavailability. The inhibitory effect of phytic acid is very dependent on dietary calcium in association with phytate and zinc. Usual calcium intakes by humans are much below those demonstrated in animals to cause phytate inhibition of dietary zinc availability.     

Zinc and immunity

Nutritional deficiency of zinc is widespread throughout the developing countries and a conditioned deficiency of zinc is known to occur in many diseased states. Zinc is known to play an important role in the immune system and zinc deficient subjects may experience increased susceptibility to a variety of pathogens. We have studied the effects of a mild deficiency of zinc on T cells in an experimental model of human zinc deficiency. We showed that T cell functions were affected adversely even when the deficiency of zinc was mild in humans. Characteristically during zinc deficiency, the serum thymulin activity (a thymic hormone) was decreased which was restored following zinc supplementation. Our studies also showed that zinc deficiency caused an imbalance between TH1 and TH2 functions. The production of IFN-g, IL-2, TNF-a (products of TH1 cells) were decreased, whereas the production of IL-4, IL-6 and IL-10 (products of TH2) were not affected during zinc deficiency. T cell subpopulation studies revealed that the CD4+ CD45RA+ to CD4+ CD45RO+ ratio was decreased as a result of zinc deficiency, suggesting that zinc may be required for the regeneration of new CD4+ T cells. We further documented that zinc deficiency decreased NK cell lytic activity and caused a decrease in the percentage of CD8+ CD73+ T cells which are known to be predominantly precursors of cytotoxic T cells. In a suitable cell culture model our studies revealed that the gene expression of a DNA synthesizing enzyme TK was affected adversely which resulted in delayed cell cycle and decreased cell growth. The above immunological consequences of zinc deficiency may be responsible for decreased cell mediated immune functions in zinc deficient subjects.     

Zinc requirements and the risks and benefits of zinc supplementation.

The adult human contains 2-3g of zinc, about 0.1% of which are replenished daily. On this basis and based on estimates of bioavailability of zinc, dietary recommendations are made for apparently healthy individuals. Absent chemical, functional, and/or physical signs of zinc deficiency are assumed indicative of adequacy. More specific data are seldom available. Changing food preferences and availability, and new food preparation, preservation, and processing technologies may require re-evaluation of past data. Conservative estimates suggest that 25% of the world's population is at risk of zinc deficiency. Most of the affected are poor, and rarely consume foods rich in highly bioavailable zinc, while subsisting on foods that are rich in inhibitors of zinc absorption and/or contain relatively small amounts of bioavailable zinc. In contrast, among the relatively affluent, food choice is a major factor affecting risk of zinc deficiency. An additional problem, especially among the relatively affluent, is risk of chronic zinc toxicity caused by excessive consumption of zinc supplements. High intakes of zinc relative to copper can cause copper deficiency. A major challenge that has not been resolved for maximum health benefit is the proximity of the recommended dietary allowance (RDA) and the reference dose (RfD) for safe intake of zinc. Present recommendations do not consider the numerous dietary factors that influence the bioavailability of zinc and copper, and the likelihood of toxicity from zinc supplements. Thus the current assumed range between safe and unsafe intakes of zinc is relatively narrow. At present, assessment of zinc nutriture is complex, involving a number of chemical and functional measurements that have limitations in sensitivity and specificity. This approach needs to be enhanced so that zinc deficiency or excess can be detected early. An increasing number of associations between diseases and zinc status and apparently normal states of health, where additional zinc might be efficacious to prevent certain conditions, point at the pharmacology of zinc compounds as a promising area. For example, relationships between zinc and diabetes mellitus are an area where research might prove fruitful. In our opinion, a multidisciplinary approach will most likely result in success in this fertile area for translational research.     

Estimating the Global Prevalence of Inadequate Zinc Intake from National Food Balance Sheets: Effects of Methodological Assumptions

Background

The prevalence of inadequate zinc intake in a population can be estimated by comparing the zinc content of the food supply with the population’s theoretical requirement for zinc. However, assumptions regarding the nutrient composition of foods, zinc requirements, and zinc absorption may affect prevalence estimates. These analyses were conducted to: (1) evaluate the effect of varying methodological assumptions on country-specific estimates of the prevalence of dietary zinc inadequacy and (2) generate a model considered to provide the best estimates.

Methodology and Principal Findings

National food balance data were obtained from the Food and Agriculture Organization of the United Nations. Zinc and phytate contents of these foods were estimated from three nutrient composition databases. Zinc absorption was predicted using a mathematical model (Miller equation). Theoretical mean daily per capita physiological and dietary requirements for zinc were calculated using recommendations from the Food and Nutrition Board of the Institute of Medicine and the International Zinc Nutrition Consultative Group. The estimated global prevalence of inadequate zinc intake varied between 12–66%, depending on which methodological assumptions were applied. However, country-specific rank order of the estimated prevalence of inadequate intake was conserved across all models (r = 0.57–0.99, P<0.01). A “best-estimate” model, comprised of zinc and phytate data from a composite nutrient database and IZiNCG physiological requirements for absorbed zinc, estimated the global prevalence of inadequate zinc intake to be 17.3%.

Conclusions and Significance

Given the multiple sources of uncertainty in this method, caution must be taken in the interpretation of the estimated prevalence figures. However, the results of all models indicate that inadequate zinc intake may be fairly common globally. Inferences regarding the relative likelihood of zinc deficiency as a public health problem in different countries can be drawn based on the country-specific rank order of estimated prevalence of inadequate zinc intake.     

Xanthine oxidoreductase in respiratory and cardiovascular disorders

In addition to its critical role in purine metabolism, xanthine oxidoreductase (XOR) has been implicated in the development of tissue oxidative damage in a wide variety of respiratory and cardiovascular disorders such as acute lung injury, ischemia-reperfusion injury, atherosclerosis, heart failure, and arterial hypertension. Although much remains to be clarified about the regulation and signaling pathways of this enzyme, it is quite evident from abundant investigation in animal models and some human trials that XOR inhibition can favorably alter critical disease processes and impact outcomes. From promising bench-to-bedside data, a better understanding of this enigmatic enzyme is emerging. However, the positive findings related to XOR inhibition need to be confirmed in large-scale, well-designed clinical trials. This will hopefully provide new opportunities for therapeutic intervention. This article reviews the available evidence involving XOR in oxidative states with specific emphasis on respiratory and cardiovascular diseases.     

Reference Values for Serum Zinc Concentration and Prevalence of Zinc Deficiency in Adult Iranian Subjects

Zinc, as an essential trace element for health, plays various biological roles in human body functions. Serum zinc reference values are essential for assessing zinc-associated abnormalities and the prevalence of zinc deficiency. This study aims at determining age- and sex-specific reference values for serum zinc concentrations in adult Iranian subjects. Serum zinc concentration was measured by flame atomic absorption spectrometry in 4,698 adult subjects, aged 20?C94?years, randomly selected from the population of the Tehran, Lipid, and Glucose Study. After application of exclusion criteria, reference values for serum zinc were determined in 2,632 apparently healthy subjects according to guidelines of the International Federation of Clinical Chemistry (nonparametric method). Dietary zinc was assessed in 2,906 individuals, of which 1,685 were healthy subjects, using a validated semiquantitative food frequency questionnaire. Reference values for serum zinc concentrations ranged between 9.6 and 31.6, 8.9 and 29.9, and 9.3 and 30.8???mol/L in men, women, and the total population, respectively. Prevalence of serum zinc deficiency was 3.0 and 2.4?% in men and women, respectively (p?=?0.267); in men, but not in women, the prevalence increased significantly with age (p for trend <0.001). Of the total participants, 10.3?% (6.5 men and 3.8?% women, p?<?0.01) had lower zinc intake compared to dietary reference intakes. The zinc density of the population was 6.3?mg/1,000?kcal. In conclusion, this study presents reference values for serum zinc concentration in adult Iranian subjects for both sexes and different age groups. Prevalence of serum zinc deficiency and dietary zinc inadequacy seems to be lower in Iranians, compared to some other populations.     

Regulation of the adaptation to zinc deficiency in plants

The molecular mechanisms by which plants sense their micronutrient status, and adapt to their environment in order to ensure a sufficient micronutrient supply, are poorly understood. Zinc is an essential micronutrient for all living organisms. when facing a shortage in zinc supply, plants adapt by enhancing the zinc uptake capacity. The molecular regulators controlling this adaptation were recently identified. in this mini-review, we highlight recent progress in understanding the adaptation to zinc deficiency in plants and discuss the future challenges to fully unravel its molecular basis.Key words: adaptation, zinc deficiency, biofortification, molecular regulators, plant nutritionIn an increasingly populated world, agricultural production is an essential element of social development. Agriculture is the primary source of all nutrients required for human life, and nutrient sufficiency is the basis for good health and welfare of the human population.¹ Soils with zinc deficiency are widespread in the world, affecting large areas of cultivated soils in India, Turkey, China, Brazil and Australia,^2,3 making zinc the most common crop micronutrient deficiency.⁴ In addition, risk of inadequate zinc diet and zinc malnutrition are estimated to affect one-third of the global human population, i.e., around two billion people.⁵ Most affected are people living in developing countries, where diets are rich in cereal-based foods. Cereal grains are rich in phytate, which is a potent anti-nutrient, limiting micronutrient bioavailability.⁶ Zinc deficiency in crop production can be easily ameliorated through zinc fertilization, making agronomic biofortification an important strategy,³ however in the poorer regions, the required infrastructure to provide a reliable supply of zinc fertilizers of sufficient quality, is often not available. In those situations, biofortified crops, in which the zinc status of crops is genetically improved by selective breeding or via biotechnology, offer a rural-based intervention that will more likely reach the population.⁷ Different traits can be targeted to developing such improved crops, such as plant zinc deficiency tolerance, zinc use efficiency and the accumulation of zinc in edible parts. However, insufficient knowledge on the molecular mechanisms and the regulation of the zinc homeostasis network in plants is a serious bottleneck when pursuing zinc biofortification.     

Ileal Paneth cells and IgA system in rats with severe zinc deficiency: An immunohistochemical and morphological study

Summary Morphological abnormalities in Paneth cells occur in patients with acrodermatitis enteropathica, a chereditary disease associated with zinc deficiency; furthermore, rat Paneth cells contain large amounts of zinc. This study was conducted to assess the effect of severe zinc deficiency in Sprague-Dawley rats on various parameters of Paneth cells. Morphology at both the light microscopical and ultrastructural levels, Paneth cell numbers per crypt and the intracellular distribution of lysozyme were not altered by zinc deficiency. A weak correlation (r=+0.38,P=0.05) was noted between ileal zinc concentration and numbers of IgA-containing Paneth cells per crypt. These findings indicate that the morphological abnormalities noted in human Paneth cells in patients with acrodermatitis enteropathica cannot be reproduced by experimental severe zinc deficiency in rats. Furthermore, these generally negative findings suggest that the severe diarrhoea often associated with zinc deficiency is not attributable to abnormalities induced in Paneth cells by zinc deficiency.     

Interrelationships between zinc and immune function

Zinc deficiency is a common nutritional problem observed both in human and in animal populations that has profound effects on host defense mechanisms. Using the young adult mouse as a model, it has been demonstrated that a moderate period of suboptimal zinc causes thymic atrophy, lymphopenia, and alterations in the proportions of the various subsets of lymphocytes and mononuclear phagocytes. As a result, antibody-mediated responses to both T cell-dependent and T cell independent antigens are significantly reduced. Cytolytic T cell responses, natural killer (NK) cell activity, and delayed-type hypersensitivity (DTH) reactions are also depressed. Suboptimal zinc during in utero development of mice causes persistent states of immunodeficiency in the offspring that can even be transferred to subsequent generations. In regard to human immunological consequences of zinc deficiency, patients with the genetic disorder of zinc absorption, acrodermatitis enteropathica, also exhibit atrophic thymuses, lymphopenia, anergic DTH responses, and reduced NK cell activity. Patients suffering from sickle cell anemia or uremia with associated deficiencies in zinc exhibit similar immune deficiencies. An additional outcome of these studies has been shown to be an essential cofactor for thymulin, one of the thymic hormones. Furthermore, addition of zinc salts to culture can polyclonally activate lymphocytes as well as augment responses to mitogens in adjuvant-like manner.     

Vitamin E and neurological function: lessons from patients with abetalipoproteinaemia

For many years the role of vitamin E (α-tocopherol) in human nutrition was uncertain, but it is now recognised that this fat soluble vitamin is necessary for normal neurological structure and function. The evidence came initially from patients with abetalipoproteinaemia, then from patients with other chronic and severe fat malabsorptive states, from patients with an isolated deficiency of vitamin E without generalised fat malabsorption, and from comparative neuropathological studies in vitamin E deficient man, monkey and rat. Severe and chronic vitamin E deficiency in the different patient groups resulted in a characteristic neurological disorder which progressed to crippling and blindness. Early and appropriate supplementation with vitamin E can prevent the development of all the neurological signs and symptoms, and treatment of patients with established lesions invariably halts and in some cases can reverse the neuropathy. These clinical and pathological findings raise a number of basic questions regarding the function of vitamin E in neural tissues which are currently being addressed in an animal model.