Emerging Concepts in Nutrient Needs

ABSTRACT

Dietary reference intakes (DRIs) are quantitative, nutrient intake–based standards used for assessing the diets and specific nutrient intakes of healthy individuals and populations and for informing national nutrition policy and nutrition programs. Because nutrition needs vary by age, sex, and physiological state, DRIs are often specified for healthy subgroups within a population. Diet is known to be the leading modifiable risk factor for chronic disease, and the prevalence of chronic disease is growing in all populations globally and across all subgroups, but especially in older adults. It is known that nutrient needs can change in some chronic disease and other clinical states. Disease states and/or disease treatment can cause whole-body or tissue-specific nutrient depletion or excess, resulting in the need for altered nutrient intakes. In other cases, disease-related biochemical dysfunction can result in a requirement for a nonessential nutrient, rendering it as conditionally essential, or result in toxicity for a food component at levels usually tolerated by healthy people, as seen in inborn errors of metabolism. Here we summarize examples from a growing body of literature of disease-altering nutrient requirements, supporting the need to give more consideration to special nutrient requirements in disease states.

Nutrient Requirements in Disease Prevention and Management

In 2010, diet was shown to be among the leading risk factors for disability and nonfatal diseases, including chronic diseases, in the United States (1). In 2014, it was estimated that 60% of adult Americans had ≥1 chronic condition and 40% had multiple chronic diseases (2). Historically, the outcomes of investigations of uncomplicated nutritional deficiencies, those that can be resolved by increasing the intake of a single nutrient in virtually all individuals, have been used to establish Dietary Reference Intakes (DRIs). Diseases of nutrient deficiency arise when there is insufficient access to the amount of nutrient necessary for normative physiological function. Diseases of nutrient deficiency are now uncommon in the more developed parts of the world, but there is increasing interest in the role that diet can play in the prevention and management of chronic diseases.

DRIs in the United States and Canada reflect intake levels that sustain adequate nutriture for physiological function in healthy populations. DRIs have been derived for all essential nutrients and some nonessential food components, e.g., fiber. These established intake levels support physiological processes, including metabolism, and prevent diseases of deficiency and/or reduce risk of chronic disease onset. The DRIs provide guidance for meeting nutrient needs and avoiding excess intakes from diets and the food system, respectively, for both individuals and populations. The near disappearance of essential nutrient deficiencies in the United States and Canada and the widespread use and regulatory applications of reference values in public health, clinical, and educational settings document the efficacy of the guidance provided by DRIs, the impact of the evidentiary evaluations on which the DRI values are based, and their important roles in health and related regulatory applications.

DRIs consist of various reference values that enable the assessment of the dietary intakes and nutritional status of healthy individuals and/or populations. The Estimated Average Requirement (EAR) is defined as the intake level needed by half of the healthy individuals within a defined population or subgroup to meet a specified outcome. The Recommended Dietary Allowance (RDA) is defined as the average daily level of intake that meets the requirements of 97.5% of healthy people within a defined population, and its value is 2 SDs above the EAR, based on the assumption that expected interindividual variation is distributed normally. The tolerable upper intake level (UL) is the highest maximum daily habitual intake level that is unlikely to cause adverse health effects (3–5). The DRIs also include recommendations for macronutrient and energy intakes. There are excellent reviews on the processes and considerations for establishing DRIs (6) and their use in nutrition policy and programs and public guidance (7).

In response to the growing burden of chronic disease, the National Academies of Sciences, Engineering, and Medicine developed a consensus report, Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease, which addresses the challenges of establishing DRIs and presents a framework for using chronic disease endpoints (8). This report was guided substantially by an earlier report sponsored by Health Canada and several health-related US federal agencies (9).

Major challenges in the use of chronic disease endpoints for DRI development include the following: 1) lack of consistent evidence, including data from clinical trials; 2) the need to expand the number of classifiable subgroups for setting DRIs, because the sole use of chronic disease endpoints does not identify all individuals at risk for nutrient inadequacy; 3) the recognition that endpoints cannot necessarily be assigned to single nutrients, given the strong interactions and interdependencies of multiple nutrients, behaviors, and environmental factors that affect specific, and at times multiple, chronic diseases in at-risk groups as well as nutrient adequacy in healthy populations; and 4) uncertainties regarding the effect of age on chronic disease initiation and progression (7).

In response to the recognition that chronic diseases, once established, may alter nutrient requirements, which if unmet may lead to nutrient-related disease comorbidities, the National Academies of Sciences, Engineering and Medicine published workshop proceedings, Examining Special Nutritional Requirements, in 2018 (10). This review highlights examples whereby disease can alter nutrient requirements and the need to consider nutrient needs in chronic disease populations, and serves as a starting point to review the current knowledge regarding the effects of disease on nutritional requirements.

Functional and Clinical Endpoints for Establishing Requirements

Identifying appropriate endpoints and outcomes to define nutrient intake requirements is fundamental to the establishment of DRIs for healthy populations and Special Nutrient Requirements (SNRs) in disease states, as discussed in detail below (Figure 1). “Adequate for what” health or physiological outcome(s) is the initial consideration for the process of establishing a DRI (11). The considerations for the choice of endpoints can include defined clinical health outcomes, such as avoidance of a cardiac event; validated surrogate biomarkers for which nutrient intake is directly related to a health outcome along a causal pathway (12), such as hypertension as a surrogate for cardiovascular events; and nonvalidated intermediate functional biomarkers that are not necessarily related to a clinical outcome but that have been reliably and substantially reported to have a dose–response relationship with nutrient intake levels and targeted physiological response(s). Validated and nonvalidated surrogate biomarkers should have a high predictive value relating intake levels to physiological or health responses in individuals and/or populations of interest. The use of validated surrogate and functional biomarkers as outcomes can be complemented with nutritional status biomarkers for which there are dose–response relations of nutrients (or other food components) to the amounts of a targeted substance in blood or tissue. In the case of healthy individuals and populations, DRIs are defined for each food substance of interest relative to a selected endpoint or combination of endpoints, and DRI values may or may not differ depending upon the selection of endpoints chosen for a given food substance and targeted individual characteristics such as age group, sex, physiologic condition (e.g., pregnancy). ULs are derived for some food components when an intake level above a defined threshold results in an adverse clinical outcome or a biomarker of toxicity.

FIGURE 1.

Generic analytic framework applicable to assessment of nutrients. The representation illustrates how a nutritional exposure (intake) can directly affect a chronic disease outcome (Path I); how a nutritional exposure can directly affect a validated surrogate outcome that is on the causal pathway of a chronic disease outcome (Path II); how a nutritional exposure can directly affect a nonvalidated intermediate marker that is associated with a chronic disease outcome (Path III); how a nutritional exposure can directly affect a marker of nutrient intake that is associated with a chronic disease outcome (Path IV) and/or a surrogate outcome (Path V). Reproduced with permission from Russell et al, 2009 (11).

Outcomes selected to establish intake recommendations can differ by subgroups. For example, folate intake recommendations for adults are based on the outcome of maintaining blood folate concentrations, an indicator of folate status, and minimizing serum homocysteine, a functional indicator of folate metabolism (13, 14). There is a separate folate intake recommendation for women of childbearing age that is specific for a particular form of folate, folic acid, and based on a unique health outcome, namely the prevention of neural tube defects in infants, a developmental anomaly that is preventable by appropriately timed, relatively high intakes of folic acid by at-risk individuals (15–17). In contrast, even within the same subgroup, nutrient requirements can be based on multiple outcomes, culminating in a single DRI. In the case of vitamin D, the requirement for older adults is based on 2 outcomes: a biochemical marker of nutritional status (circulating 25-hydroxyvitamin D) and the functional health outcomes of reductions in fractures and bone mineral density loss (18, 19). These examples demonstrate the importance of identifying and assigning relevant and sometimes distinctive outcomes to defined subgroups within a population and the possibility that DRI values may differ depending upon the targeted subgroup, outcome, and associated measures of that outcome. In the folate example, clearly primary prevention (prevention of disease onset) is the targeted aim. The vitamin D example illustrates the blurring of the goals of primary and secondary prevention (reducing the impact/severity of the disease) and the use of the present DRI framework for those purposes. Both examples demonstrate the high bar and complexities likely to be faced in future derivations of SNRs (as described below in “Clinical Conditions That Affect Nutritional Status and Function”), particularly when new categories of reference values are likely to be relevant to secondary and possibly tertiary prevention (managing the effects of disease progression). Importantly, both secondary and tertiary prevention strategies most often target individuals rather than populations.

The Challenge of Specific Population Subgroups and the Concept of Precision Nutrition

When nutrient requirements for specific, identifiable subgroups within a population do not fall within 2 SDs of the population-based EAR, distinct DRIs may be established for these subgroups (20). Currently established factors that affect nutrient requirements leading to subgroup-specific DRIs include sex, age, and physiological states such as pregnancy or lactation. Environmental factors are also considered in the establishment of DRIs. Vitamin D status is determined not only by dietary intake but also by nondietary exposure to sunlight (21), which contributes to endogenous vitamin D synthesis and which is accounted for in the DRI for vitamin D (18). Increasingly, other biological and environmental factors have been suggested to modify nutritional requirements of healthy individuals to a degree that indicates the need for consideration of additional specific subgroup classifications. For example, controlled feeding trials have demonstrated that the current RDA for folate is not sufficient to meet the nutrient requirement for some individuals who are homozygous for a common genetic polymorphism in the methylenetetrahydrofolate dehydrogenase reductase gene (677TT; MTHFR) (22). The MTHFR genotype impact on biomarkers of folate requirement is further exacerbated in some populations, especially men of Mexican American heritage (23). Emerging evidence also suggests that higher folate intakes are required to lower blood arsenic levels in arsenic-exposed populations (24). Obesity, which is strongly influenced by “obesogenic environments” (25), characterized by abundant calorie availability and limited opportunity for physical activity or significant enticements to remain inactive, influences status indicators of several nutrients, with vitamin D insufficiency in obese individuals and those with type II diabetes being among the most well-documented examples (26). However, it is not established whether the magnitude of the effects is sufficient to recommend specific dietary requirements for otherwise healthy obese and overweight individuals (27). Nonetheless, limiting nutrient recommendations to a decreasing proportion of the general population, i.e., healthy individuals, leaves multiple challenges unaddressed when the prevalence of diet-related unhealthy conditions is high and/or growing significantly.

In summary, there is an increased awareness that many factors affect nutritional requirements, raising the potential need to establish DRIs for additional subgroups other than age, sex, and pregnancy/lactation. Among these factors are the increase in age-related chronic diseases driven by changes in population demographics, increased use of pharmaceuticals, and increases in certain at-risk behaviors, among others. In addition to effects of age-associated chronic diseases on nutrient requirements, age-associated decay of biological networks in the absence of disease may also directly affect nutrient requirements and disease susceptibility. Hence, the increasing ability to identify and classify specific population subgroups for whom population-based DRIs may not apply is challenging the concept of relying solely on population-based nutrient recommendations. This challenge is stimulating innovation and interest in the concept of individualized nutrient requirements and personalized nutrition, following the paradigm of precision medicine (28).

Clinical Conditions That Affect Nutritional Status and Function

Data on specific patient populations are not used to derive DRIs for healthy populations because of the known effects of disease on biomarkers of nutrient status and function. In 1972, Herbert described the 5 possible causes of nutrient deficiencies: 1) insufficient intake, 2) impaired absorption, 3) augmented requirement because of disease or parasitization, 4) increased rates of turnover due to increased rates of degradation or excretion, or 5) inadequate utilization (29). In addition, 6) wasting due to chronic inflammation, associated with conditions including chronic gastrointestinal (30) or kidney disease (31), is also now known to create nutrient deficiencies. The DRIs provide guidance for the nutrition needs of healthy populations but address only 1 of the 6 causes of nutrient deficiency listed above, namely insufficient intake. Still unknown is the degree to which DRIs do not apply to clinical populations, including patients with chronic disease, who represent nearly half of the United States adult population (32). However, it is known that chronic disease or other clinical conditions affect nutritional needs and that meeting such special needs may assist in secondary and tertiary prevention of disease, through mechanisms that include tissue regeneration. There are currently no consensus guidelines for estimating the nutritional needs of many clinical populations, with the rare exceptions being guidelines for patients with renal disease and patients being treated with total parenteral nutrition. Disease and its treatment can affect biomarkers of whole-body nutritional status and function (such as serum biomarkers and serum vitamin levels) but may also deplete nutrient concentrations in specific tissues in the absence of whole-body nutritional deficiencies. Some clinical conditions that are known to alter nutritional status indicators are described below to illustrate the impact of disease and its treatment on nutritional status and nutrient requirements.

Chronic inflammation and cancer

The impact of inflammation on decreasing the amounts of plasma pyridoxal phosphate (PLP) , which is a biomarker of vitamin B6 status in numerous patient populations, was recently reviewed (33). Vitamin B6 supplementation is not effective in increasing plasma PLP in critically ill patients with systemic inflammation. For patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), the severity of the disease inversely correlates with PLP plasma levels. However, the decrease in plasma PLP occurs with no indication of a functional vitamin B6 deficiency in RA patients, based on measurements of PLP-dependent enzyme activity. Inflammation may cause increased rates of vitamin B6 catabolism during the acute-phase immune response, as well as redistribution of available vitamin B6 away from the plasma and liver, but not muscle, with increased vitamin B6 uptake at sites of inflammation. As such, these effects of increased vitamin B6 catabolism, tissue redistribution, and tissue sequestration may result in tissue-specific vitamin B6 depletion with or without whole-body nutritional deficiency. The health consequences resulting from altered vitamin B6 metabolism and physiology during inflammation are not known, nor is it known if patients with inflammatory disease exhibit clinical benefit from vitamin B6 supplementation.

The effect of systemic inflammation on lowering the amounts of blood nutrients is also observed for several lipid-soluble vitamins, including vitamin D. Plasma 25-hydroxyvitamin D concentrations were shown to decrease 5 to 30 d after elective knee arthroplasty in patients who exhibited a systemic inflammatory response, leading the authors to conclude that this biomarker of vitamin D status is not a reliable indicator in the presence of chronic systemic inflammation (34). As a negative acute-phase reactant, serum 25-hydroxyvitamin D is not a validated biomarker of vitamin D status in chronic inflammation, and it has been suggested that hypovitaminosis D is a consequence, and not a cause, of chronic inflammatory diseases (35). In addition to these illustrative examples, it is important to note that there are numerous additional examples of inflammation-induced perturbations in nutrient homeostasis. The effects of both acute (36, 37) and chronic (36, 38) inflammation on biomarkers of iron status and iron metabolism have been reviewed elsewhere, and design of effective nutritional interventions to combat these changes is an area of active investigation. Similarly, inflammation and the associated acute-phase response are known to alter vitamin A intake, absorption, and transport (36, 39).

Nutrient deficiencies can arise in cancer patients (40). Increased rates of folate catabolism have been observed under select physiological and pathological conditions, including cancer (41). Folate catabolism refers to the irreversible degradation of the cofactor into a pterin derivative and para-aminobenzoylglutamate (42). The increased requirements of cancer cells for DNA synthesis and cell proliferation, and the increased rates of folate catabolism and turnover, may create localized, tissue-specific folate deficiency (43).

Infectious disease

Perturbed macronutrient metabolism and increased macronutrient catabolism in response to infectious diseases has been recognized for >100 y, and the mechanisms leading to increased blood glucose and release of amino acids from muscle as a result of infection are well characterized in animal models and in humans (44–46). There are also other more recent examples of increased micronutrient requirements as a response to infection. Vitamin D status is often compromised in HIV-infected patients. Supplementation of HIV-infected young adults with 7000 IU cholecalciferol, an amount that is >10-fold higher than the RDA (47), which improved both whole-body vitamin D status and also improved markers of HIV status by increasing immune function and decreasing HIV viral load (48).

Trauma and surgery

In critical care patients, metabolic imbalances are not always chronic, but may also be time limited, episodic, or transient and progress with the course of a disease or its treatment. This pattern of imbalances may also be translated into periods when “conditionally essential” nutrients must be provided exogenously. Under normal physiological conditions, these nutrients may be synthesized by the body in adequate amounts, but under the stress of trauma, surgery, or disease pathology, this synthesis may become rate limiting for the optimal function of organs or for tissue repair. It is for such reasons that medical foods have been specially formulated, taking into account factors beyond simple digestion, absorption, and transportation of traditionally defined nutrients.

Surgical insults and trauma have been shown to decrease the amounts of plasma arginine and to put patients at increased risk of infection, especially those who are undernourished, (49, 50). In these situations, arginine becomes a conditionally essential nutrient. Trials in surgical and trauma patients administering nutritional interventions containing very high doses of arginine indicate that arginine supplementation reduces infections in these populations (50). A systematic review of arginine supplementation in patients undergoing elective surgeries that included 28 trials reporting per patient infectious complications indicated a significant reduction in infection risk as a result of perioperative arginine supplementation (RR: 0.59; 95% CI: 0.50, 0.70; P < 0.00001) (49). The effects of arginine on T-cell proliferation and function and the interactions between T-cells and myeloid suppressor cells and the mechanisms whereby arginine affects immunity have been eloquently reviewed elsewhere (50). Importantly, arginine supplementation does not reduce the risk of infection in all types of critically ill, nonsurgical hospitalized patients. Furthermore, arginine does not affect immune function in the absence of immune stimulation. This example highlights the importance of specifying populations where SNRs exist.

Drug–nutrient interactions

Pharmaceutical agents for chronic disease management can induce disease-related malnutrition. Thiamine deficiency is highly prevalent in patients with congestive heart failure resulting from the regular use of loop diuretics, which have been shown to induce thiamine deficiency in controlled animal studies and in human clinical trials (51). Thiamine supplementation was found to improve cardiac function, as indicated by a net change in left ventricular ejection fraction, in a meta-analysis of randomized, double blind, placebo-controlled trials (52, 53). The results of these studies suggest a potential benefit for inclusion of thiamine in congestive heart failure therapies that include angiotensin-converting enzyme inhibitors, β-blockers, loop diuretics, and ω-3 fatty acids.

Both observational studies and placebo-controlled randomized trials support a relation between metformin use and vitamin B12 deficiency that is sometimes associated with folate deficiency (54–62). Metformin is a pharmaceutical agent that is widely prescribed for the treatment of type 2 diabetes. Metformin use is associated with vitamin B12 deficiency in about 30% of its users (63). Peripheral neuropathy affects up to 60% of diabetic patients (64), and results from the deterioration of small nerve fibers, both myelinated A-fibers and unmyelinated C-fibers (64). Peripheral neuropathy is also a neurological manifestation of vitamin B12 deficiency. In a prospective case-control study of diabetic patients, those taking metformin exhibited exacerbated symptoms of peripheral neuropathy whereas those not taking metformin did not, though there was no significant effect of metformin use on nerve conduction velocity (61). The etiology of diabetic peripheral neuropathy is not well understood, but its etiology is likely multifactorial and may involve several metabolic pathways. In addition, the role of vitamin B12 in diabetic peripheral neuropathy has not been rigorously assessed (65).

Inborn errors of metabolism

Inborn errors of metabolism usually present at birth when they are detected through newborn screening programs and result from severe genetic mutations that compromise the transport, processing, stability, or metabolism of nutrients (66). For example, mutations in other folate-related genes, including methylenetetrahydrofolate reductase (67) and dihydrofolate reductase (67), and mutations in genes that result in brain serine deficiency may also affect brain folate levels. Serine is a major source of one-carbons for folate-mediated one-carbon metabolism. Deficiencies in these enzymes are known to result in increased rates of folate catabolism and turnover because unstable forms of folate accumulate when their activity is impaired (43). These disorders can create primary and secondary nutrient deficiencies that impair cognitive and other neurological function, growth and development, behavior, and susceptibility to disease, as reviewed recently (68).

Differences in the nutritional requirements for those born with inborn errors of metabolism and those for healthy individuals including the following: 1) the restriction of certain dietary components to avoid the toxic accumulation of metabolic intermediates, as seen in the dietary management of phenylketonuria (69); 2) the need for high intakes of specific nutrients to overcome nutrient transport or processing defects (70, 71); and 3) the requirement for novel “conditionally essential” nutrients such as metabolites that are depleted as a result of the genetic mutation. The design and use of nutritional interventions for inborn errors of metabolism, including the use of dietary supplements, medical foods, and dietary restrictions, was the subject of a recent review (68).

Loss of barrier function

Under normal conditions, the blood–brain barrier (BBB) regulates the exchange of nutrients and other constituents between the blood and cerebrospinal fluid (CSF) of the central nervous system (72), creating a microenvironment that supports neurological functions (73). The barrier deteriorates and becomes more permeable with age, and is compromised by chronic inflammation, hypoxia, and diabetes mellitus (72). BBB deterioration and/or dysfunction compromises the supply of nutrients to the brain and prevents protein and small molecule leakage from the blood into the CSF (74), a process which is accelerated in the early stages of Alzheimer disease (75). Some small molecules such as folate that are maintained at higher amounts in the CSF relative to the serum are at risk for depletion as a result of compromised BBB integrity or function (76). More than 30 neurological and psychiatric diseases have been associated with cerebral folate deficiency (CFD) (67). Late-onset Alzheimer dementia (AD) patients were also shown to have significantly lower levels of folate in the CSF (77, 78). Importantly, several studies have provided evidence for a tissue-specific central nervous system vitamin deficiency that is exacerbated by, and/or independent from, whole-body deficiency. These studies indicate that brain-specific nutrient deficiencies can occur in the absence of whole-body nutrient deficiencies (79, 80). Treatments for CFD resulting from genetic mutations include oral ingestion of ≥60 mg folic acid/d, which is not always successful. However, parenteral (5 mg, twice weekly) or oral folinic acid (0.5–20 mg · kg⁻¹ · d⁻¹) is well tolerated and normalizes CSF folate concentrations, resulting in improvement in neurological outcomes and white matter morphology (67, 80, 81).

Autoimmunity and nutrient transport

Celiac disease, a common autoimmune disorder of the small intestine, is characterized by injury of the mucosal tissue of the small intestine, inflammation, and compromised intestinal nutrient transport with associated malabsorption, leading to whole-body nutrient deficiencies (82). Celiac disease is primarily observed in adults and arises from gluten ingestion in genetically sensitized individuals. Celiac patients also can exhibit neuropsychiatric comorbidities, including depression, anxiety, and other complications that can resolve with dietary modifications (83). Celiac disease is also a risk factor for neuropathy (84). A randomized clinical trial found that celiac patients have baseline plasma homocysteine concentrations significantly higher than those of control subjects. Treatment with high-dose folate and vitamin B12 supplementation normalized blood homocysteine concentrations in these patients, as well as significantly improving patient anxiety and depression (85).

In states of nutrient deficiency associated with chronic disease, nutrition interventions that restore nutrient status and physiological functions support the concept of Special Nutritional Requirements (SNRs) (Figure 2). Disease states, and/or pharmaceutical use in disease management, can alter the level of nutrient intake required to maintain indicators of adequate nutrient status and/or functional status characteristic of nourished healthy populations. Nutrition interventions can also be used to correct a functional deficit caused by the disease, such as the need for “conditionally essential” nutrients or elevated nutrient intakes to address barrier dysfunction. In these cases, the nutritional intervention is designed to compensate for or correct a biochemical impairment to restore normal physiological functioning required for health. This compensation may be independent of whole-body nutritional status indicators used for healthy populations but related to other indicators, including tissue-specific nutrient status indicators and direct clinical outcomes.

FIGURE 2.

Factors and their associated pathways that affect human nutritional requirements in disease.

Addressing SNRs

Nutritional states in which SNRs may be present are associated with chronic diseases in classifiable groups of patients and may include the following conditions: 1) consistent failure to achieve adequate nutrient status, demonstrated nutrient deficiency or excess when achieving RDA-level nutrient intakes, and required nutrient intake levels significantly above or below an RDA to achieve nutrient adequacy or avoid toxicity; 2) improvement in a clinical condition with intake of a particular nutrient or nutrient combination at levels above (or below) the RDA independent of established criteria for nutritional adequacy; and 3) a “conditionally essential” nutrient requirement or restriction for a metabolite or food component that is not required from exogenous sources by healthy individuals. For the second scenario, medical food formulations compensate for identifiable biochemical impairments and restore normal physiological functioning required for a specified health outcome. Medical food formulations are intended for use in dietary management to meet patient medical needs and address their nutrient requirements (86). A medical food, as defined in section 5(b) (3) of the Orphan Drug Act [21 USC 360ee(b) (3)], is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” (87). Such foods often are designed to meet tertiary prevention goals.

Clinical and population heterogeneity underlies most chronic conditions. This heterogeneity creates challenges in establishing nutrient requirements of individual patients because of the need to avoid both nutrient deficiencies and excesses in the presence of narrower than usual windows of adequacy. Clinical populations should be grouped by disease etiology to best ensure that special nutritional needs are met. For example, arginine supplementation mitigates infection risk in surgical and trauma patients, but not in critically ill patients afflicted by other conditions (50). Similarly, the necessity for accurate patient classification to fully meet a patient's distinctive nutritional needs was also recently highlighted for the treatment of newborn patients with cblC deficiency, a genetic condition that impairs vitamin B12 processing (88, 89). Patients with cblC deficiency comprise a subgroup of patients exhibiting methylmalonic acidemia (MMA), a condition that results from a functional vitamin B12 deficiency. MMA is diagnosed by elevated methylmalonic acid in blood due to 1 of several inherited genetic disorders that can be fatal if not treated. Patients with cblC deficiency also exhibit neuropsychiatric symptoms, including dementia, which resolves with vitamin B12 therapy (71, 90). The primary cause of MMA is mutations in the methylmalonyl CoA mutase enzyme. In addition to MMA, patients with cblC deficiency exhibit homocystinuria due to an inability to synthesize methionine from homocysteine, which requires vitamin B12–dependent methionine synthase activity. Recent results from a clinical trial demonstrated that treatment of cblC patients with medical foods designed for general MMA patients places them at risk for iatrogenic methionine deficiency, which can adversely affect growth and cognitive development (89). The study's authors stress the need for rigorous, well-controlled clinical investigations that test the efficacy and safety of medical foods. Such investigations are scant at present. Although this case is specific to patient classifications based on genetic etiology, the paradigm of understanding the impact of disease etiology on the design of efficacious treatments can be extended to nearly all clinical populations.

Conclusions and Future Directions

Research over the past decades indicates that nutrient intake levels affect chronic disease prevalence and severity. Current initiatives to increase the use of endpoints for primary chronic disease prevention in the DRI framework have the potential to provide more relevant guidance to health-conscious individuals, and to directly address the continuing rise in rates of noncommunicable disease and its associated public health burden in populations. While current approaches to dietary guidance address chronic disease primary prevention, there is an increasing recognition that additional guidance is needed with respect to establishing nutrient intake levels that target secondary and tertiary prevention of chronic disease. Specifically, DRIs based on chronic disease endpoints that target primary, secondary and tertiary prevention are needed for the improved management of clinical populations.

These findings are supported by a body of evidence from clinical studies that demonstrate disease can influence whole-body and/or isolated, tissue-specific nutrient status and function, and that meeting SNRs in disease can play a beneficial role in the support of patients with diseases unrelated to dietary etiologies. Although the concept of SNRs is still in its infancy, further development of this concept has the potential to benefit the growing clinical populations who live with serious chronic disease but for whom the DRIs may not apply. Equally important is the establishment of the underlying biological mechanisms that support the concept of an SNR. Consideration of nutrition in chronic disease from a prevention, management, and regenerative perspective offers the potential to address disease etiology comprehensively and better align public health and medical approaches with nutrition guidance and policy.

Notes

Supported by Public Health Service grant R37DK58144 to PJS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) or the National Institutes of Health.

Author disclosures: The authors report no conflicts of interest.

The 10th Workshop on the Assessment of Adequate and Safe Intake of Dietary Amino Acids was held in Tokyo, Japan, 19-20 November 2019. The Conference was sponsored by the International Council on Amino Acid Science (ICAAS).

Supplement Sponsorship and Disclosure: This article appears as part of the supplement ''10th Amino Acid Assessment Workshop," sponsored by the International Council on Amino Acid Science (ICAAS). The guest editors of the supplement are D Bier, L Cynober, S Morris, P Stover, M Kadowaki, and R Elango. The travel and accommodation costs of the guest editors were paid in full by ICAAS. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition.

Abbreviations used: BBB, blood-brain barrier; CFD, cerebral folate deficiency; CSF, cerebrospinal fluid; DRI, dietary reference intakes; EAR, estimated average requirement; IBD, inflammatory bowel disease; MMA, methylmalonic academia; PLP, pyridoxal-phosphate; RA, rheumatoid arthritis; RDA, recommended dietary allowance; SNR, special nutrient requirement; UL, tolerable upper intake level.