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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Page xiii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop. Washington, DC: The National Academies Press. doi: 10.17226/25164.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Examining Special Nutritional Requirements in Disease States PROCEEDINGS OF A WORKSHOP Anne Brown Rodgers, Rapporteur Food and Nutrition Board Health and Medicine Division PREPUBLICATION COPY: UNCORRECTED PROOFS

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and the Academy of Nutrition and Dietetics; the American Society for Nutrition; the Crohn’s and Colitis Foundation; Health Canada; the National Institutes of Health; and the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25164 Additional copies of this publication are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2018 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Examining Special Nutritional Requirements in Disease States: Proceedings of a Workshop Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25164. PREPUBLICATION COPY: UNCORRECTED PROOFS

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY: UNCORRECTED PROOFS

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo. PREPUBLICATION COPY: UNCORRECTED PROOFS

PLANNING COMMITTEE ON EXAMINING SPECIAL NUTRITIONAL REQUIREMENTS FOR DISEASE STATES—A WORKSHOP1 BARBARA O. SCHNEEMAN (Chair), Professor Emerita, University of California, Davis PATSY M. BRANNON, Professor, Division of Nutritional Sciences, Cornell University, Ithaca, NY STEVEN K. CLINTON, Professor, Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus ALEX R. KEMPER, Chief of the Division of Ambulatory Pediatrics, Nationwide Children’s Hospital, Columbus, OH ERIN MACLEOD, Director of Metabolic Nutrition, Division of Genetics and Metabolism, Children’s National Health System, Washington, DC BERNADETTE P. MARRIOTT, Professor, Division of Gastroenterology and Hepatology, Department of Medicine, and Professor, Military Division, Department of Psychiatry, Medical University of South Carolina, Charleston PATRICK J. STOVER, Vice Chancellor and Dean for Agriculture and Life Sciences at Texas A&M AgriLife, College Station DAVID L. SUSKIND, Professor of Pediatrics, Division of Gastroenterology, University of Washington, Seattle GARY D. WU, Ferdinand G. Weisbrod Professor in Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia Health and Medicine Division Staff MARIA ORIA, Study Director ALICE VOROSMARTI, Research Associate CYPRESS LYNX, Senior Program Assistant ANN L. YAKTINE, Director, Food and Nutrition Board 1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteur and the National Academies. v PREPUBLICATION COPY: UNCORRECTED PROOFS

Reviewers This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: John W. Erdman, Emeritus, University of Illinois at Urbana-Champaign Denise M. Ney, University of Wisconsin–Madison Robert M. Russell, Emeritus, Tufts University School of Medicine David L. Suskind, Seattle Children’s Hospital Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by A. Catherine Ross, The Pennsylvania State University. She was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteur and the National Academies. vii PREPUBLICATION COPY: UNCORRECTED PROOFS

Contents ACRONYMS AND ABBREVIATIONS 1 INTRODUCTION AND WORKSHOP OVERVIEW 1-1 Organization of This Proceedings of a Workshop, 1-3 Welcoming Remarks, 1-4 What Defines a Special Nutritional Requirement?, 1-5 The Underlying Biological Processes of Special Nutritional Requirements, 1-9 Moderated Panel Discussion and Q&A, 1-12 References, 1-15 2 ADDRESSING NUTRIENT NEEDS DUE TO LOSS OF FUNCTION IN GENETIC DISEASES 2-1 Understanding the Basis of Nutritional Needs in Phenylketonuria, 2-1 Nutritional Inadequacies in Mitochondrial-Associated Metabolic Disorders, 2-4 Contribution of Nutrients in Complex Inborn Errors of Metabolism: The Case of Methylmalonic Aciduria, 2-9 Lessons Learned: What Is Known About Nutrition Management for Inborn Errors of Metabolism, 2-12 Moderated Panel Discussion and Q&A, 2-14 References, 2-15 3 DISEASE-INDUCED LOSS OF FUNCTION AND TISSUE REGENERATION 3-1 Examples of Gastrointestinal Dysfunction and Malabsorption of Nutrients: Intestinal Failure, 3-1 Examples of Gastrointestinal Dysfunction and Malabsorption of Nutrients: Cystic Fibrosis, 3-4 Nutritional Requirements for Inflammatory Bowel Disease, 3-7 Blood–Brain Barrier Dysfunction and Resulting Brain Nutrient Deficiencies, 3-10 Macro- and Micronutrient Homeostasis in the Setting of Chronic Kidney Disease, 3-12 Moderated Panel Discussion and Q&A, 3-15 References, 3-18 4 DISEASED-INDUCED DEFICIENCY AND CONDITIONALLY ESSENTIAL NUTRIENTS IN DISEASE 4-1 Arginine as an Example of a Conditionally Essential Nutrient: Sickle Cell Anemia and Surgery, 4-1 Traumatic Brain Injury: Pathophysiological Mechanisms and Potential Nutrient Needs, 4-5 ix PREPUBLICATION COPY: UNCORRECTED PROOFS

Metabolic Turnover, Inflammation, and Redistribution: Impact on Nutrient Requirements, 4-7 Moderated Panel Discussion and Q&A, 4-8 References, 4-10 5 BUILDING THE EVIDENCE BASE: RESEARCH APPROACHES FOR NUTRIENTS IN DISEASE STATES 5-1 Type and Strength of Evidence Needed for Determining Special Nutrient Requirements, 5-1 Identification and Validation of Biomarkers in Disease States, 5-7 Innovative Causal Designs for Efficacy: What Type of Evidence is Needed?, 5-8 Example of a Complex Disease: Inflammatory Bowel Disease, 5-11 Example of a Complex Disease: Cancer, 5-13 Moderated Panel Discussion and Q&A, 5-16 References, 5-19 6 EXPLORING POTENTIAL OPPORTUNITIES 6-1 Panel Discussion, 6-2 Open Discussion and Q&A, 6-5 Closing Remarks, 6-6 Reference, 6-9 APPENDIXES A WORKSHOP AGENDA A-1 B SPEAKER AND MODERATOR BIOGRAPHICAL SKETCHES B-1 x PREPUBLICATION COPY: UNCORRECTED PROOFS

Boxes, Figures, and Table BOXES 1-1 Statement of Task, 1-2 1-2 What Constitutes a Distribution Outside of Dietary Reference Intakes?, 1-8 FIGURES 1-1 Traditional Dietary Reference Intakes: Distribution of requirement and risk of adverse outcome in a “healthy” population, 1-5 1-2 Classifying and evaluating human nutrient needs, 1-10 1-3 Comparison of Dietary Reference Intakes and special nutritional needs, 1-12 2-1 Mitochondrial disease: Molecular pathways affected by genetic disorders, 2-5 2-2 Novel treatment strategies in mitochondrial disease, 2-8 2-3 Daily protein intake by patients with methylmalonic aciduria mut subtype, sorted by age, 2-11 3-1 Prevalence of micronutrient deficiencies during parenteral nutrition weaning, 3-3 3-2 Survival in children with cystic fibrosis at various weight-for-age percentiles, 3-6 3-3 Influence of disease on whole-body nutrient status and tissue-specific nutrient status, 3-10 4-1 The arginine metabolome, 4-2 4-2 Mechanisms of vasculopathy and endothelial dysfunction, 4-4 5-1 Risk assessment approach to setting Dietary Reference Intake values, 5-2 5-2 Establishing adequacy: Biomarkers of exposure on the causal pathway, using folate as an example, 5-3 5-3 Nutrient requirements in disease states, 5-4 5-4 Example of complex relationships in cystic fibrosis, 5-5 5-5 The relationship among diet, the gut microbiota, and inflammatory bowel disease, 5-12 TABLE 3-1 Summary of Nutrient Requirements in Chronic Kidney Disease, 3-13 xi PREPUBLICATION COPY: UNCORRECTED PROOFS

Acronyms and Abbreviations AI Adequate Intake AND Academy of Nutrition and Dietetics ASN American Society for Nutrition ATP adenosine triphosphate BBB blood–brain barrier BMI body mass index BOND Biomarkers of Nutrition for Development BRINDA Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia CF cystic fibrosis CFD cerebral folate deficiency CFTR cystic fibrosis transmembrane conductance regulator CHOP Children’s Hospital of Pennsylvania CRP C reactive protein CSF cerebrospinal fluid DHA docosahexaenoic acid DNA deoxyribonucleic acid DoD Department of Defense DRI Dietary Reference Intake EAR Estimated Average Requirement EEN exclusive enteral nutrition EPA eicosapentaenoic acid FDA U.S. Food and Drug Administration GFR glomerular filtration rate GI gastrointestinal GMP glycomacropeptide GRADE Grading of Recommendations, Assessment, Development and Evaluation IBD inflammatory bowel disease IOM Institute of Medicine MELAS mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes MMA methylmalonic aciduria xiii PREPUBLICATION COPY: UNCORRECTED PROOFS

NHANES National Health and Nutrition Examination Survey NIH National Institutes of Health NOS nitric oxide synthase PAH phenylalanine hydroxylase PEW protein energy wasting Phe phenylalanine PICO Population, Intervention, Comparisons, Outcomes PKU phenylketonuria PLP pyridoxal phosphate RCT randomized controlled trial RD registered dietitian RDA Recommended Dietary Allowance TBI traumatic brain injury UL Tolerable Upper Intake Level UMDF United Mitochondrial Disease Foundation WCRF-AICR World Cancer Research Fund and the American Institute for Cancer Research WHO World Health Organization xiv PREPUBLICATION COPY: UNCORRECTED PROOFS

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The amount of nutrients required by an individual is determined by a number of physiological processes, including absorption, metabolism, stability, and bio-activation. These processes determine nutrient needs and provide variations in requirements in the population. All have modifiers and sensitizers, such as sex, genetics, pregnancy, age, pharmaceuticals, toxins, food matrix, and epigenetics. Disease can also be a major modifier of these processes. In April 2018, the National Academies of Science, Engineering and Medicine convened a workshop in order to explore the evidence for special nutritional requirements in disease states and the medical conditions that cannot be met with a normal diet. Participants explored the impact a disease state can have on nutrient metabolism and nutritional status, and attempted to close informational gaps. This publication summarizes the presentations and discussions from the workshop.

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