Choline Information Council Comment to USDA/HHS Regarding the 2015 Dietary Guidelines Advisory Committee Report

May 4th, 2015
May 1, 2015
Mr. Richard D. Olson, MD, MPH
Office of Disease Prevention and Health Promotion
U.S. Department of Health and Human Services
Choline Information Council Comment to USDA/HHS Regarding the 2015 Dietary Guidelines Advisory Committee Report
The Choline Information Council appreciates the opportunity to provide the sponsoring agencies with comments regarding the 2015 Dietary Guidelines Advisory Committee (DGAC) Report.  The Choline Information Council was founded to promote awareness of the need for choline as an essential nutrient.  It promotes choline awareness to consumers, health professionals, and the trade industry; working closely with multi-channel media to communicate about the need for choline and its availability from food and dietary supplements.

Recognition of Choline as Underconsumed by Americans
The DGAC called out in their report that the majority of Americans fail to achieve the Adequate Intake (AI) for choline.  Based on review of the most recent NHANES/WWEIA data, the DGAC considered choline intake relative to the AI, along with fiber, potassium, and vitamin K.  They reported that 10% of the population typically consumed choline above the AI (Fig D 1.2), meaning that 90% fail to typically consume the AI for choline.  The DGAC also determined that a low proportion of the population had fiber and potassium intakes above the AI.  Of the nutrients identified with low intake relative to the AI, only potassium and fiber were classified as underconsumed (Figure D1.2).  

The Committee also reviewed the adequacy of USDA’s Food Pattern Modeling.  The USDA Food Patterns are intended to represent the types and amounts of foods that will provide nutrients sufficient to meet IOM nutrient recommendations and Dietary Guidelines for Americans recommendations.  The Food Patterns are updated every 5 years during the deliberations of the Dietary Guidelines Advisory Committee, and are presented to the Committee for their assessment of the Food Patterns’ adequacy. As part of the update, amounts recommended from each food group may be modified to reach all or most of the specified goals.  The nutrients for which adequacy goals are not met in almost all patterns are potassium, vitamin D, vitamin E, and choline.  In evaluation of the specific food patterns, the Committee found that if no dairy is consumed, the modeling analysis shows that levels of calcium, magnesium, iron, vitamin A and riboflavin, drop below 100 percent of goals, and intake levels of potassium, vitamin D and choline also drop substantially.

The DGAC added fiber and potassium to their list of underconsumed nutrients, along with vitamin D, vitamin E, magnesium, calcium, vitamin A and vitamin C.   Choline was recognized as a nutrient with 90% of the population failing to consume the AI amount, but the DGAC failed to make any public health recommendations for choline.  The DGAC also found choline to be a nutrient not meeting its adequacy goals in almost all USDA Food Pattern models, but again chose not to make any recommendations intended to increase the amount of choline consumed by Americans.

Evidence of Adverse Health Effects from Lack of Choline
Of the shortfall nutrients, the DGAC classified calcium, vitamin D, fiber, and potassium as nutrients of public health concern “because their underconsumption has been linked in the scientific literature to adverse health outcomes”.  However, there is objective evidence that underconsumption of choline is also linked to adverse health outcomes, including fatty liver and neural tube defects in pregnant women.  Choline has been shown to support positive cognitive effects, and supports memory development in children and improved academic performance.  The IOM Report in 1998 declared an Adequate Intake (AI) for choline since it felt at the time there were “few data to assess whether a dietary supply of choline is needed at all stages of the life cycle, and it may be that the choline requirement can be met by endogenous synthesis at some of these stages” (Food and Nutrition Board, IOM, 1998).  However, since that time there has been published evidence of effects of choline deficiency in individuals across the life cycle and important individual epigenomic variation in choline metabolism and requirements.

There is strong evidence that adequate choline supports normal liver functions and helps to prevent nonalcoholic fatty liver disease (NAFLD) and fatty liver, either as a result of choline deficiency or alcohol consumption.
Choline functions in liver health through a variety of mechanisms.  These include prevention of abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum stress (Corbin and Zeisel, 2012).

Choline’s role as part of the phospholipid phosphatidylcholine is critical in healthy liver function.  It is a primary structural component of the phospholipid membrane of all cells.  This phospholipid is also needed in the construction of very low density lipoproteins (VLDL), which function in fat transport. 

Rodents fed choline–methionine-deficient diets develop fatty liver.  They also progress to develop liver fibrosis and hepatocarcinoma (Corbin and Zeisel, 2012).  Dietary intake of methyl donors, including choline, influences the methylation of DNA and histones, thereby altering the epigenetic regulation of gene expression.  The liver is the major organ within which methylation reactions occur, and many of the hepatic genes are involved in pathways for the development of fatty liver, hepatic fibrosis, and hepatocarcinomas are epigenetically regulated (Mehedint MG and Zeisel SH, 2013).

The effect of choline on preventing fatty liver has been evident for some time.  Research published in 1958 reported the positive effects of choline on liver health.  A single dose of choline administered to choline-deficient animals increased the oxidation of liver fat as well as the synthesis of liver phosphatide P32 (Zilversmit et al, 1958). 
NAFLD affects one-third of U.S. adults; one-half of obese men; and 11% of adolescents. One in 10 have liver disease.  
Obesity, Rx medications, especially statins, and alcohol consumption along with high incidence of cirrhosis of the liver, especially in Europe, will continue to draw attention to liver health. Canada, the EU, and the UK published government warning reports on liver health in 2013.  Alcohol consumption in the U.S. is at an all-time high.

Pregnancy and Lactation:
Choline plays a critical role in brain development in the fetus and in infants, especially in the development of the hippocampus and basal forebrain, known to regulate memory.  Choline also acts like folate in preventing neural tube defects in fetal development.

Folate, choline, and betaine serve as hydroxy methyl group donors, and are all important in the prevention of neural tube defects (NTD) which results in birth defects, including anencephaly or spina bifida.  These defects occur early in pregnancy, between the 21st and 27th days after conception, when many women do not realize that they are pregnant.

There is clear evidence of suboptimal intakes of choline for most individuals, especially pregnant and lactating women.  Human studies show that women in the highest quartile of choline intakes had a 72% lower risk of NTD-affected pregnancy and those with lowest levels of serum choline had 2.4-fold greater risk (Shaw et al, 2009).   Large amounts of choline are delivered to the fetus across the placenta; choline concentration in amniotic fluid is 10-fold greater than that present in maternal blood.  Plasma or serum choline concentrations are significantly higher in pregnant women than non-pregnant women, and are six to seven-fold higher in the fetus and newborn than in adults (Shaw et al, 2009). Human milk is rich in choline, therefore, needs in lactation are greatest and maternal stores are generally depleted for extended periods of time.
Choline is critical to healthy cognitive function.  Choline is a critical component of the building blocks of the nervous system, including neurotransmitters that form the mechanistic basis for memory.  Choline is part of the messaging system of the brain, and functions directly and indirectly in brain activities and in cognitive development for the fetus and infant. 

Specifically, choline is a precursor to the neurotransmitter acetylcholine. Choline also functions as part of phosphatidylcholine, a structural component of the phospholipid membrane of all cells, including glial and neuronal cells.  Choline is a precursor to sphingomyelin, which is important to the integrity of neurons and in the metabolism of molecules, including diacylglycerol and ceramide, which function in intracellular signaling. 

Choline supports the communication between neurons in the brain and promotes better availability of neurotransmitters for signaling within the brain. The availability of choline at different stages of human development and aging appears to be significant in improving the density and branching of dendrites, which results in more contact points for neurotransmission (McCann et al, 2006).  It also supplies the raw materials for the enzyme that generates the neurotransmitter, acetylcholine.  Choline availability affects the strength of neuronal response to stimulation in the parts of the brain responsible for memory, including the hippocampus. 

The level of choline in the brain is directly affected by its levels in plasma, which is supported through dietary intake and supplementation.  Free choline reaches the brain by crossing the blood-brain barrier (Wurtman et al, 2009).  Choline status can also up- or down-regulate the activity of enzymes that synthesize acetylcholine, the neurotransmitter (Cermak et al, 1998).  Inadequate choline intake compromises neurotransmission, and/or nerve tissue and cellular integrity as the body works to maintain a supply of free choline to the brain. 

Gestational choline supply has a significant influence on the structure and cholinergic functions of the fetal and infant nervous system.  Choline availability to a fetus appears to have an enduring significance in that individual at an advanced age (Meck et al, 2008).  Choline is needed before birth as a precursor for the structural phospholipids needed to construct the membranes of cholinergic neurons (Wurtman et al, 2009). 

Choline supplementation and deprivation studies have been conducted in cell culture and animal models.  Researchers have examined the nutrient’s role in cell differentiation and migration in the hippocampus and cortex, regions of the brain that regulate learning and memory.  The availability of prenatal choline corresponds to morphological change and increase in the overall size of cholinergic neurons in the basal forebrain, which facilitates neurotransmission.  The neurophysiological development of the hippocampus is directly affected by choline intake as well (Li et al, 2004).  In the hippocampus, choline affects the level of nerve growth factor, a factor that is important in the refinement of neural connections that enhance communication and improve learning and memory functions (Jones et al, 1999).  Synaptic connections continue to be formed in the hippocampus and basal forebrain in the months and years after birth (Jones et al, 1999), so choline nutrition in infancy and childhood are critically important.
Benefits of pre- and post-natal choline availability are seen in behavioral studies in animal species (McCann et al, 2006).  Performance enhancement in offspring provided sufficient choline early in life is most evident in better execution of complex memory-related tasks, particularly those involving visio-spatial and serial learning and memory (Li et al, 2004).

Cognitive decline in aging is due in part to oxidative events, including an increase in reactive oxygen species, spurring the oxidation of low density lipoproteins, DNA damage, the rampant growth of smooth muscle cells, and aggregation of platelets that result in occlusive damage to tissues and organs.  Such oxidative events occur when high levels of homocysteine are present.  Homocysteine is a metabolically-generated amino acid which is directly and inversely associated with choline intake (Cho et al, 2006).  Homocysteine may be a biomarker, by-product, risk factor, or active agent of biochemical change; and it is widely thought to have a role in cognitive decline in normal aging, and may atrophy parts of the brain hippocampus and cortex (Garcia and Zanibbi, 2004).  Failure in cognitive functions that occur in aging include reduced synthesis of the neurotransmitter acetylcholine, breakdown or insufficient repair of neurons, loss of myelin and dendrite branches, and cell death in the hippocampus..  If one or more of these factors affecting memory loss may be modulated by choline intake, then choline intake in normal aging may help to maintain cognitive function in the otherwise healthy aging individual. 

Choline Should Be Included in Policy Recommendations
There appears to be a paradoxical lack of health professional and media attention to this vital nutrient.  Although the 2010 and 2015 Dietary Guidelines advisory committees called out choline as a nutrient that is currently underconsumed, the 2010 Dietary Guidelines made no mention of choline.   

Adverse effects from choline deficiency have long term impact on health, affecting memory and cognitive function throughout life, liver health, and the potential for neural tube defects in women.  Similar health effects have launched nationwide food fortification programs, i.e., folate fortification of enriched flour.  Additionally, choline supports optimal mental performance throughout a lifetime, and may prevent cognitive decline in aging.

The Choline Information Council asks the U.S. Department of Health and Human Services and U.S. Department of Agriculture to include policy recommendations in the 2015 Dietary Guidelines for Americans for increasing choline intake through foods; and when intake through foods is not likely, to support intake with choline dietary supplements.  It is time for nationwide and international attention to choline and the impact of choline deficiency. 
Cho E, Zeisel SH, Jacques PF, Selhub, J, Dougherty L, Colditz, GA (2006) Dietary choline and betaine assessed by food frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr 83:905-11.
Corbin KD and Zeisel SH (2012) Curr Opin Gastroenterol March 28(2):159-165.
Elias MF, Sullivan LM, D’Agostino RB, Elias PK, Jacques PF, Selhub J (2005) Homocysteine and cognitive performance in the Framingham Offspring Study: Age is important. Am J Epidemiol 162(7):644-53.
Food and Nutrition Board, Institute of Medicine (1998) Dietary Reference Intake: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic acid, Biotin, and Choline. National Academy of Sciences, pp 390-422.
Garcia A and Zanibbi K (2004) Homocysteine and cognitive function in elderly people. Can Med Assoc J 171(8):897-904.
Jones III JP, Mech WH, Williams CL, Wilson WA, Swartzwelder HS (1999) Choline availability to the developing rat fetus alters adult hippocampal long-term potentiation. Dev Brain Res 118:159-67.
Li Q, Guo-Ross S, Lewis DV, Turner D, White AM, Wilson WA (2004) Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol 91:1545-55.
McCann JC, Hudes M, Ames BN (2006) An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosc Behav Rev 30:696-712.
Meck MH, Williams CL, Cernak JM, Blusztajn JK (2008) Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integ Neurosc 1
Mehedint MG and Zeisel SH (2013) Choline’s role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Met Care 16(3):339-45.
Shaw GM, Finnell, RH, Blom, HJ, Carmichael, SL, Vollset, SE, Yang, W, and Ueland, PM (2009) Choline and risk of neural tube defects in a folate-fortified population. Epidemiol 20(5):714-719
Wurtman RJ, Cansev M, Ulus IH. (2009) Choline and its products acetylcholine and phosphotidylcholine. In: Tettamani G, Goracci G editors. Handbook of Neurochemistry and Molecular Neurobiology: Neural Lipids. 3 ed. New York: Springer pp. 443-500.
Zilversmit DB and Diluzio NR (1958) The role of choline in the turnover of phospholipids.  Am J Clin Nutr 6(3):235-41.