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Key points
- People with ARFID have atypical levels of appetite-regulating hormones, including ghrelin and cholecystokinin.
- Despite similar symptoms, people with anorexia nervosa have significantly higher ghrelin levels after fasting than people with ARFID.
- While ghrelin and cholecystokinin are best known for their involvement in appetite, they regulate other functions, too, such as anxiety.
Avoidant/restrictive food intake disorder (ARFID) is an eating disorder with symptoms of food restriction and avoidance. Importantly, it is not driven by body shape and weight concerns, which distinguishes it from anorexia nervosa (AN).
Unfortunately, we are only just beginning to understand what biological factors contribute to ARFID development. Doing so is important, however, as ARFID can have a negative impact on a person’s physical and mental health, as well as their life quality.1
Hormone research is one field exploring the neurobiology of ARFID. A particular goal of this research is to understand how dysfunction in hunger and fullness cues might play a role in ARFID onset and maintenance.
Cholecystokinin (CCK) and Fullness
Several different bodily chemicals determine satiety. One of these chemicals is cholecystokinin (CCK), a hormone produced in the small intestine that regulates digestion and feelings of fullness.11 When food enters the small intestine, CCK is released from intestinal cells; once released, CCK fits like a key into proteins called receptors. These CCK receptors are specifically designed for CCK, and they are located throughout the digestive system and brain.
When CCK fits into a receptor located in the gut, it stimulates the release of bile and digestive enzymes from the gallbladder and pancreas; these digestive juices flow into the small intestine and break down food. To make sure that the small intestine is uninterrupted during this process, CCK limits food from entering it; it also reduces our appetites by sending signals from the gut to the brain’s “eating” center, the hypothalamus, via blood or a pathway called the vagus nerve.2 Once these signals reach the brain, CCK is released from cells in the hypothalamus, which makes us feel full.3
Ghrelin and Hunger
Ghrelin has an opposing function to CCK. When the stomach is empty, ghrelin is released as a way to stimulate eating by inducing hunger.5 Like CCK, it acts as a key for specific ghrelin receptors located throughout the digestive system and brain. Also like CCK, ghrelin in the gut communicates with the brain via the blood and vagus nerve.6 In the digestive tract or brain, when a ghrelin “key” fits into a ghrelin receptor, different effects occur, one of which is hunger.12
CCK, Ghrelin, and ARFID
Only a couple of studies have explored the role of CCK and ghrelin in ARFID.
Dr. Murray and colleagues at Harvard Medical School are the first to investigate CCK in ARFID.4 For their study, they recruited 125 men and women between the ages of 10 and 23 years old. Of these participants, 83 persons had a diagnosis of ARFID or subclinical ARFID, while 42 persons were considered "healthy."
The study required that participants fast and then provide a blood sample, from which CCK levels were measured. They did this because, following a food fast, CCK levels are typically low, as digestion isn't occurring. However, in this study it was found that participants with ARFID, on average, had more than three times the levels of circulating CCK compared to participants without ARFID.4 This suggests that there is something "unique" about the digestive process for people with ARFID and they, possibly, don't experience fullness in the same way that people without ARFID do.
In a separate 2021 study, Dr. Becker and colleagues explored the role of ghrelin in ARFID.7 For their study, they recruited women ages 10-22 years old who had either been diagnosed with ARFID or anorexia nervosa (AN). They also included participants without either disorder for comparison.
Participants in this study were asked to fast and then provide a blood sample. In typical cases, ghrelin levels will be high after a fast, as ghrelin stimulates hunger. People with AN, which is another food restricting disorder, have been shown to have very high levels of ghrelin after a fast.7 Consequently, Becker et al. (2021) were expecting individuals with ARFID to show similarly high levels of ghrelin after a fast.
What they found, however, surprised them. In their study, participants with ARFID had significantly lower levels of ghrelin after a fast than participants with AN.7 Compared to people without either disorder, participants with ARFID had slightly higher levels of CCK, though this wasn't significant. This suggests that the severity of ghrelin abnormalities might be a distinguishing factor between ARFID and AN, where individuals with ARFID have slightly elevated levels of ghrelin after a fast, but not to the extent of those with AN.
Conclusions
While it’s tempting to conclude that these hormone abnormalities are what’s driving food restriction in ARFID, it’s not that simple. This is because CCK and ghrelin are involved in other bodily functions, including anxiety,8 panic,8 reward,8; 9 and motivation.10 It could be that atypical levels of these hormones in ARFID are not contributing to the disorder by altering feeding cues. For example, in the Murray study, CCK was not significantly associated with subjective ratings of appetite.4 Therefore, CCK and ghrelin dysregulation could be contributing to ARFID by increasing anxiety or altering motivation to eat. In fact, anxiety has a demonstrated role in food avoidance in ARFID.13
Future studies should continue measuring hormones involved in eating behavior for ARFID research. However, more acknowledgment should be given to investigating the roles of these hormones in functions beyond feeding cues.
References
1) Hay, P., Mitchison, D., Collado, A., González-Chica, D., Stocks, N., & Touyz, S. (2017). Burden and health-related quality of life of eating disorders, including Avoidant/Restrictive Food Intake Disorder (ARFID), in the Australian population. Journal of Eating Disorders, 5. https://doi.org/10.1186/s40337-017-0149-z.
2) Raybould, H.E. (2009). Mechanisms of CCK signaling from gut to brain. Current Opinion in Pharmacology, 7, 570-574. doi: 10.1016/j.coph.2007.09.006.
3) Schick, R.R., Schusdzziarra, V., Yaksh, T.L., & Go, V. L. (1994). Annals of the New York Academy of Sciences, 713, 242-254. doi: 10.1111/j.1749-6632.1994.tb44072.x.
4) Burton Murray, H., Becker, K.R., Harshman, S., Breithaupt, L., Kuhnle, M., Dreier, M.J.,…& Lawson, E.A. (2022). Elevated fasting satiety-promoting cholecystokinin (CCK) in Avoidant/Restrictive Food Intake Disorder compared to healthy controls. The Journal of Clinical Psychiatry, 83. doi: 10.4088/JCP.21m14111.
5) Howick, K., Griffin, B.T., Cryan, J.F., & Schellekens, H. (2017). From belly to brain: Targeting the ghrelin receptor in appetite and food intake regulation. International Journal of Molecular Sciences, 18. doi: 10.3390/ijms18020273.
6) Date, Y. (2012). Ghrelin and the vagus nerve. Methods in Enzymology, 514, 261-269.
7) Becker, K.R., Mancuso, C., Dreier, M.J., Asanza, E., Breithaupt, L., Slattery, M.,…& Lawson, E.A. (2021). Ghrelin and PYY in low-weight females with Avoidant/Restrictive Food Intake Disorder compared to Anorexia Nervosa and healthy controls. Psychoneuroendocrinology, 129. doi: 10.1016/j.psyneuen.2021.105243.
8) Rotzinger, S., & Vaccarino, F.J. (2003). Cholecystokinin receptor subtypes: Role in the modulation of anxiety-related and reward-related behaviors in animal models. Journal of Psychiatry & Neuroscience, 28, 171-181.
9) Perelló, M., & Zigman, J.M. (2012). The role of ghrelin in reward-based eating. Biological Psychiatry, 72, 347-353.
10) Skiibicka, K.P., Hansson, C., Alvvarezz-Crespo, M., Friberg, P.A., & Dickson, S.L. (2011). Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience, 180, 129-137.
11) Ballinger, A.B., & Clark, M.L. (1994). L-Phenylalanin releases cholecystokinin (CCK) and is associated with reduced food intake in humans: Evidence for a physiological role of CCK in control of eating. Metabolism, 43, 735-738.
12) Zaloga, G.P. (2005). Ghrelin, diet, and pulmonary function. Chest Journal, 128, 1084-1084. https://doi.org/10.1378/chest.128.3.1084.
13) Harris, A.A., Romer, A.L., Hanna, E.K., Keeling, L.A., LaBar, K.S., Sinnott-Armstrong, W.,...& Zucker, N.L. (2019). The central role of disgust in disorders of food avoidance. International Journal of Eating Disorders, 52, 543-553.
