Regulating Satiety in Bulimia Nervosa: The Role of Cholecystokinin

Abstract

PURPOSE

Individuals with bulimia nervosa (BN) report altered perceptions in hunger, fullness, and satiety. This article reviews the role of cholecystokinin (CCK), a satiety-producing hormone, in the regulation of binge eating in those who suffer from BN.

CONCLUSION

Studies have shown that CCK is decreased in individuals with BN when compared with healthy controls. Decreased CCK functioning may contribute to impaired satiety and thus binge eating in this patient population. Depending on the macronutrient composition of food choices, CCK release can be differentially influenced. For instance, protein is a potent stimulator of a CCK response. Eating more protein-rich meals increases the release of CCK, increasing satiety and ending a meal.

PRACTICE IMPLICATIONS

Knowledge of CCK functioning and the utility of manipulating the macronutrient composition of meals may inform standard behavioral treatment strategies for those who suffer from BN.

Bulimia nervosa (BN) is a chronic and debilitating illness that is characterized by extreme alterations in eating patterns, including an irresistible urge to overeat followed most often by self-induced vomiting. BN’s core defining feature, repeated binge-eating episodes and the associated compensatory behavior, has a serious impact on the psychological and physiological well-being of this vulnerable and often chronic population. The fourth edition, text revision of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2000) identifies the cardinal feature of BN as binge eating, characterized as a “loss of control” during repeated episodes of eating excessively large amounts of food (American Psychiatric Association, 2000, p. 594). This is followed by inappropriate purging or nonpurging compensatory behaviors. Purging behaviors include self-induced vomiting, laxative abuse, diuretic abuse, and misuse of enemas. Nonpurging behaviors include fasting, strict dieting, or excessive exercising in an effort to maintain or lose weight. To meet diagnostic criteria, binge-eating and purging behaviors must occur at a minimum frequency of two times per week over the course of 3 months.

This disorder often begins in adolescence and can persist through adulthood. Research suggests that BN is more common in young women than men, and is genetically linked (Bulik et al., 2003), with an estimated 1% lifetime prevalence (Hudson, Hiripi, Pope, & Kessler, 2007). Commonly, depression, anxiety, and substance use disorders co-occur with bulimia (Steinhausen & Weber, 2009) and can result in significant role impairment (Hudson et al., 2007) and a substantial economic burden (Simon, Schmidt, & Pilling, 2005). A pervasive devalued self-worth (including loathing of body weight and shape) is characteristic of BN. Common premorbid characteristics of impulsivity (Wolfe, Jimerson,& Levine, 1994), dysregulated emotions (Kaye, Bulik, Thornton, Barbarich, & Masters, 2004), low self-esteem, early menarche, dieting, and being criticized by others concerning their eating habits (Fairburn, Welch, Doll, Davies, & O’Connor, 1997) may contribute to the vulnerability and expression of this disorder. Individual risk factors can include genetic and familial vulnerabilities to dieting, obesity, psychiatric disorders, and substance misuse disorders (Fairburn & Harrison, 2003). Affected individuals are likely to maintain normal weight despite fluctuations and a decreased metabolic rate (Birketvedt et al., 2006). Food restriction and dieting generally precede episodes of binge eating; however, these attempts are generally futile against the cycle of repeated binge purge episodes (Beumont, 2002).

Comorbid medical conditions ensue with persistent illness. Teeth can become eroded secondary to the direct repeated exposure to gastric acids following a vomiting episode (Milosevic, 1999). The most frequent compensatory behavior, self-induced vomiting (Reba et al., 2005), can further compromise electrolyte status, requiring careful monitoring of specific laboratory values to avert complications (Wolfe, Metzger, Levine, & Jimerson, 2001). Surprisingly, even when individuals affected by BN present for routine medical care and/or eating disorder-related symptomatology, this illness often goes undetected (Johnson, Spitzer, & Williams, 2001) as patients may underreport symptoms secondary to shame, guilt, and/or a desire to retain this aberrant eating behavior.

Less than half of those affected by BN seek treatment (Hoek & Van Hoeken, 2003) and less than 50% of those in treatment achieve a full and lasting response (Fairburn, 2002; Steinhausen & Weber, 2009). For example, cognitive–behavioral therapy (the most widely accepted and studied) results in less than 50% of individuals achieving full remission, and the only one Federal Drug Administration-approved medication, fluoxetine, merits a 40% success rate (American Psychiatric Association Workgroup on Eating Disorders, 2006). Finally, outcome studies show that at least one third of individuals who previously recovered were likely to relapse and over two thirds maintain eating disorder symptoms of clinical severity (Fairburn, Cooper, Doll, Norman, & O’Connor, 2000).

Binge Eating and Satiety

The biobehavioral aspects of binge eating are multifaceted and not fully understood. It has been suggested that those affected by BN may suffer from an impaired satiety system (Kissileff et al., 1996). Satiety refers to “the inhibition over hunger and further eating that arises as a consequence of food ingestion” (Blundell & Hill, 1993, p. 209). A functional satiety system consists of a complex integrative central and peripheral signaling network of positive and negative feedback mechanisms that sustain energy homeostasis (Smith & Geary, 2002). Positive feedback signals begin feeding behavior, and in response, inhibitory feedback signals terminate an episode of eating (Smith & Gibbs, 2002). If there is a dysregulation in the potency of the negative feedback signaling mechanism, meal size and duration can be enlarged. Binge eating may reflect a dysregulation in the negative feedback mechanism of the satiety system (Figure 1).

Figure 1.

Normal Eating Behavior

Initial reports from patients with BN indicate an inability to distinguish fullness at the end of a normal meal and eating patterns that alternate between severe restriction and binge eating (Pyle, Mitchell, & Eckert, 1981). While self-reports of food consumption by those with BN appear dramatic (Mitchell & Laine, 1985), studies show a direct correlation between subjective accounts and laboratory measurement of food intake (Walsh, Kissileff, Cassidy, & Dantzic, 1989). Clinical laboratory studies show that patients with BN consume a significantly larger amount of food compared with controls (Guss, Kissilef, Walsh, & Devlin, 1994) and at a significantly more rapid pace (Zimmerli, Devlin, Kissileff, & Walsh, 2010). In contrast to healthy controls, despite eating quantifiably larger amounts of food, patients with BN reported less fullness and displayed increased motivation to eat as the meal progressed (Kissileff et al., 1996).

BN subjects consumed far fewer calories when instructed not to binge in comparison with controls (Hadigan, Kissileff, & Walsh, 1989), underscoring that persons with BN may regularly restrict when not engaged in a binge-eating episode. One plausible explanation is that due to a lack of inhibitory controls, patients artificially terminate meals in contrast to allowing the naturally occurring mechanisms of satiety to affect both meal size and duration.

These studies demonstrate a clear abnormality in eating behavior that may serve to perpetuate this incapacitating disorder.

Overview of Cholecystokinin

Researchers focused on the negative feedback mechanisms that terminate a meal are interested in the postprandial (after a meal) measurement of the hormone cholecystokinin (CCK). This well-known satiety-producing gastrointestinal hormone influences meal size and duration (Smith, 2002). CCK was originally discovered in 1928 (Ivy & Goldberg, 1928) for its ability to contract the gallbladder, and was later found to stimulate pancreatic exocrine secretion (Harper & Raper, 1943). Additional physiological actions include regulation of gastric emptying and induction of satiety. In a highly synchronized manner, CCK regulates the intake, digestion, and absorption of nutrients (Chandra & Liddle, 2007; Dockray, 2009b).

CCK is produced by the enteroendocrine cells located in the proximal mucosa of the small intestine (Chandra & Liddle, 2007). CCK-producing cells can be found in the small intestine, vagal afferent nerve fibers, and brain (Moran & Kinzig, 2004). CCK-1 receptors (previously identified as A-alimentary) are primarily located in the gastrointestinal system, whereas CCK-2 receptors (previously known as B-brain) are located in the central nervous system. It is the interactions of the CCK-1 receptors that are thought to contribute to satiety signaling (Dockray, 2009a; Moran, Ameglio, Schwartz, & McHugh, 1992).

The signal pathway that is involved with satiety begins with a robust CCK postingestive response to nutrients. After chyme (partially digested food) enters the proximal duodenum (through relaxation of the pyloric sphincter), CCK is released from the lumen mucosa into the periphery (Smith & Gibbs, 2002). CCK-1 receptor interacts with the vagus nerve projecting onto the nucleus tractus solitarius (NTS) of the hindbrain (Chandra & Liddle, 2007). Further influence extends to the arculate nucleus of the hypothalamus and the paraventricular nucleus (Rehfeld, 2004). This higher order integration evaluates inhibitory signals and metabolic state to determine energy storage needs for regulation, whereas the NTS primarily controls the amount of food eaten (Hellstrom et al., 2004). In summary, CCK stimulates the vagus nerve, which sends a robust signal to the hindbrain for the termination of a meal.

CCK and Satiety

Preclinical studies have been essential in demonstrating CCK as an integral component of the satiety system. These studies have shown that intravenous administration of CCK induced satiety in canine (Sjodan, 1972) and in rats (Gibbs, Young, & Smith, 1973). Additionally, intraperitoneal injection of CCK during sham feeding in the rat not only stopped feeding but elicited the complete behavioral sequence of satiety (Antin, Gibbs, Holt, Young,& Smith, 1975).

In humans, intravenously infused administration of CCK versus saline in a double-blind experimental fashion resulted in a decreased appetite in healthy normal- and obese-weight women (Lieverse, Jansen, Masclee, & Lamers, 1995), and an earlier termination of the meal without changes in the rate of eating or complaints of side effects in healthy lean (Kissileff, Pi-Sunyer, Thornton, & Smith, 1981) and obese men (Pi-Sunyer, Kissileff, Thornton, & Smith, 1982). Additionally, behavioral measures (postprandial visual analog satiety ratings) were positively correlated with CCK responses in healthy males (Boelsma, Brink, Stafleu, & Hendriks, 2010; Holt, Brand, Soveny, & Hansky, 1992). While initial studies showed administration of CCK reduced meal size and duration, studies using a CCK-1 receptor antagonist demonstrated an increase in caloric intake and feelings of hunger (Beglinger, Degen, Matzinger, D’Amato,& Drewe, 2001). The above evidence further illustrates the satiety-producing effects of CCK.

CCK and Satiety: BN

Individuals affected by BN consistently exhibit altered perceptions of hunger and fullness or satiety (Halmi, Sunday, Puglisi, & Marchi, 1989). A faulty satiety system fails to signal and subsequently inhibit the intake of food (Devlin et al., 1997; Kissileff et al., 1996). CCK’s postprandial measurement, compared with controls, shows a blunted response in individuals with BN (Devlin et al., 1997; Geracioti & Liddle, 1988; Keel, Wolfe, Liddle, De Young, & Jimerson, 2007; Pirke, Kellner, Friess, Krieg, & Fichter, 1994). It has been suggested that this diminished response is due to a compilation of gastrointestinal dysfunctions (Hadley & Walsh, 2003; Walsh, Zimmerli, Devlin, Guss, & Kissileff, 2003). For example, subjects with BN have an enlarged gastric capacity, diminished sensitivity to distention, and slowed gastric emptying as compared to matched healthy controls (Zimmerli, Walsh, Guss, Devlin, & Kissileff, 2006). An enlarged gastric capacity (the result of repeated binges) (Geliebter & Hashim, 2001), may take longer to fill, thereby delaying the entry of chyme into the small intestine. This slowed gastric emptying (Geliebter et al., 1992) could confound the expected robust release of CCK into the periphery (Devlin et al., 1997). A diminished CCK response to nutrients may fail to adequately signal and lead to an increased amount of food eaten or a binge episode (Figure 2).

Figure 2.

Compilation of Gastrointestinal Dysfunctions in Bulimia Nervosa

In review, individuals with BN and altered satiety maintain the following characteristics in comparison with matched healthy controls:

1. Feel out of control while repeatedly consuming a significantly greater amount of food.

2. Rate and desire to binge eat accelerates instead of decelerates as the meal progresses.

3. After eating excessively large amounts of food, report feeling less, rather than more, satiated.

4. Exhibit altered perceptions of hunger and fullness.

5. Feel more anxious, depressed, sick, and less relaxed during an episode of bingeing.

6. CCK, a satiety-producing hormone, is diminished post-prandially when compared with matched healthy controls.

Influencing CCK Response and Binge Eating

Depending on the macronutrient composition of food choices, CCK release can be differentially influenced. For instance, protein is a potent stimulator of a CCK response (Geraedts et al., 2010). Research studies have observed a hierarchy among macronutrients concerning overall satiety effectiveness in humans, with these macronutrients being protein, carbohydrates, and fats, respectively (Veldhorst et al., 2008). A recent study of healthy but overweight/obese men (N = 27) were randomized to high (HP) versus normal protein (NP) and found that the HP group exhibited improved appetite control and satiety during an energy restriction-induced weight loss (Leidy, Tang, Armstrong, Martin, & Campbell, 2010). Research suggests that protein may induce satiety by influencing the release of gut hormones such as CCK, increasing energy expenditure through thermogenesis and raising plasma amino acids concentrations (Potier, Darcel, & Tomé, 2009).

However, those individuals with BN have shown a trend toward eating dessert and snack foods (Rosen, Leitenberg, Fisher,& Khazam, 1986). Further, a carbohydrate craving has been suggested as a driving force in the perpetuation of this behavior (Hadigan et al., 1989). Research examining the utility of dietary protein compared to carbohydrate supplementation (during a 2-week period) resulted in a 62% reduction of binge-eating episodes (Latner & Schwartz, 1999). These binge-eating participants also reported less hunger and greater fullness following supplementation with protein compared to carbohydrate. The addition of protein to a carbohydrate lunch reduced the amount eaten at a subsequent meal compared to carbohydrate alone (Latner & Schwartz, 1999). This suggests that the addition of protein to a mixed-macronutrient meal may enhance the satiating efficiency of those who engage in binge eating. Latner and Wilson (2004) hypothesize that CCK may mediate the effect of protein on satiety. Further, they propose that increasing the proportion of protein in the diet may decrease the frequency of binge-eating episodes.

Conclusion

Alterations in meal termination or satiation are common abnormal findings among those individuals affected by BN. A diminished CCK response to nutrients (potentially due to disturbances in gastric function) may fail to adequately signal and lead to an increased amount of food eaten or a binge episode. This ineffective physiological response may contribute to the perpetuation and frequent relapse of this disorder. Current knowledge of satiety, CCK functioning, and the possible utility of manipulating the macronutrient composition of meals may inform standard behavioral treatment strategies.

Implications for Nursing Practice

The Latner and Wilson (2004) study suggested that CCK may mediate the effect of protein on satiety, and that increasing the proportion of protein in the diet decreases the frequency of binge-eating episodes. These researchers also suggested that protein both at the beginning of meals and across daily intake may be a protective factor preventing overconsumption. Nurses may assess the clinical utility of these claims by asking their individual patients with BN to maintain a daily food diary. As in the Latner and Wilson study, this diary would include a record of each time and place the patient ate or drank, the amount eaten, and whether the patient considered this to be a snack, meal, or binge. This record should include whether the patient vomited, engaged in other compensatory behaviors, or experienced a loss of control over eating. An assessment of the macronutrient composition (protein, carbohydrate, and fat) of these meals should be tracked for a minimum of 1 week. After developing an understanding of the individual’s usual macronutrient intake, a purposeful evaluation of the effects of increasing dietary protein may yield a decrease in binge-eating episodes. An increased understanding of the pathophysiological mechanisms underlying impaired satiety will elucidate the future direction of clinically significant treatment strategies (e. g., behavioral and pharmacological). Concerning future research, nurses could replicate, expand on Latner and Wilson’s study, or conduct a single-subject design. Further, research targeting the enhancement of postprandial CCK responsiveness may point to novel treatments for this often chronic and debilitating disorder.