What Is Known
- Eating disorders are often associated with gastrointestinal symptoms originating from the oral cavity, salivary glands, gastrointestinal tract, pancreas, and liver.
What Is New
- This is a critical and comprehensive review of the literature on the oral, salivary, and gastrointestinal manifestations of eating disorders.
Eating disorder is a term that includes several psychiatric illnesses affecting an individual's body image and relation to food. The medical complications of eating disorders may involve virtually all body systems and may be of life-threatening severity. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published in May 2013 revised the diagnostic criteria for eating disorders in an attempt to better characterize individuals having a pathologic relation with food (1). Eating disorders now include not only anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED), but also pica, rumination, and avoidant/restrictive food intake disorder (ARFID) (1). Patients with AN typically practice an obsessive restriction of food and sometimes engage in intensive physical activity to achieve weight control. Patients with BN and BED typically engage in episodic binge eating with subsequent purging by self-induced emesis and/or laxative abuse (1). AN and BN/BED are not mutually exclusive diagnoses and many patients have elements of both. The literature suggests that AN and BN/BED are a result of both psychological and environmental factors in an individual with a genetic predisposition (2). The new diagnostic classification of ARFID is distinguished from classically defined AN, BN, and BED as an eating or feeding disturbance occurring in the absence of concerns about weight or body image (1).
The medical complications of eating disorders may involve virtually any body system and may be of life-threatening severity. In this review, we will focus on the gastrointestinal (GI) tract complications of eating disorders including those arising in the oral cavity, salivary glands, GI tract, pancreas, and liver (Table 1). Although most current literature on the GI manifestations of eating disorder are based upon studies of patients with AN, BN, and BED only, it is likely that similar manifestations would occur in patients with pica, rumination, and ARFID if nutritional health is severely impacted.
ORAL AND SALIVARY MANIFESTATIONS
The oral manifestations of eating disorders most commonly arise as a consequence of nutritional deficiencies and chronic self-induced vomiting. The symptoms may be exacerbated by use of certain medications, lack of personal hygiene, and anomalous eating habits. The teeth, oral cavity, perioral tissue, and salivary glands all may be affected. The most common dental complications are erosions, caries, and periodontal disease (3,4).
Dental erosion, or perimylolysis, occurs in BN primarily on the palatal lingual surfaces of the maxillary teeth and results from purging behaviors (5,6). With chronic acid exposure from emesis, the affected teeth display a uniform, polished surface, which is in contrast to the sharply cut angled teeth seen with mechanical wear (5,7). Erosion of the enamel becomes apparent to inspection after approximately 2 years of regular emesis (8). These patients often consume acidic fluids such as sports drinks, caffeinated and carbonated beverages as well as sweetened foods, liquids, and chewing gum in their efforts to support excessive exercise, boost energy levels, and suppress appetite (5,6). The sugar and acid exposure can further promote tooth erosion and decay. The clinician may be able to distinguish between dental erosion associated with BN and that associated with chronic gastroesophageal reflux. Reflux-associated erosion typically involves the lingual and occlusal surfaces of the posterior teeth, whereas purging behaviors more often cause erosion of the lingual surfaces of the anterior teeth (9).
Gingival inflammation and periodontitis, which present with pain and erythema of the gums, are relatively uncommon problems in children. When these symptoms present, therefore, an eating disorder should be considered in the differential diagnosis (5). Palatal erythema and ulcers, especially the soft palate, can arise in individuals with purging behavior as a result of chronic acid exposure and the repeated trauma of digital induction of purging (5,10,11). Cheilosis, a stomatitis characterized by pallor and maceration of the mucosa at the angles of the mouth, can be seen in patients with BN (5).
Nutritional deficiencies resulting from eating disorders may cause perioral and periodontal disease. Vitamin C deficiency can be associated with impaired collagen synthesis and gingival inflammation (5,12). Deficiency of the B vitamins, particularly B1, B6, and B12, important in epithelial cell turnover, can present with mucosal atrophy, atrophic glossitis and glossodynia (burning sensation of the tongue) (5,13). Severe protein calorie malnutrition may cause immune dysfunction and predispose to oral opportunistic infections including oral candidiasis (14,15). The gastroenterologist should be cognizant of the oral pathologies that may occur in patients with eating disorders and early referral to a dentist is often indicated.
Dental injury can be exacerbated in patients with eating disorders by a reduction in salivary flow (5). Bulimic patients may develop sialadenosis, a noninflammatory enlargement of the salivary glands (mainly the parotids) as a result of repetitive vomiting. Despite the covert nature of bulimia, cosmetic concerns over facial swelling from enlarged parotids may encourage some patients with bulimia to seek medical care. Parotid swelling may be symmetric or unilateral. It may initially be intermittent presenting 3 to 6 days after a binge-purge episode, but it may become persistent in long-standing disease (8).
Sialadenosis is thought to result from a peripheral autonomic neuropathy, which causes an increase in salivary acinar protein synthesis and/or a disruption in release of secretory granules. The acinar cells become engorged with zymogen granules, which result in parotid hypertrophy and impairment of salivary secretion (16). Donath and Seifert (17,18) have described degenerative changes in the myoepithelial cells and postganglionic sympathetic neurons, which regulate salivary synthetic and secretory processes and suspect that these changes cause sialadenosis. Sialadenosis is characterized by diminished parotid salivary flow rate. Salivary flow rate may be further reduced by antidepressant medications (5,19). Salivary electrolyte and immunoglobulin levels are usually normal in eating disorder patients (8,20). Serum salivary amylase level is elevated in 10% to 20% of patients with sialadenosis and usually normalizes within weeks if purging behavior ceases (8).
Necrotizing sialometaplasia has been reported in association with bulimia. It is a self-limiting, necrotizing process involving the minor salivary glands, most commonly those of the hard palate (21). This disorder can resemble a malignant palatal tumor visually and on histology is characterized by necrosis and squamous metaplasia of the salivary glands (22,23). The condition is thought to arise as a result of palatal ischemia, possibly from chronic exposure to ice chips or chronic vomiting (23).
Gastrointestinal symptoms in patients with eating disorders present a difficult clinical problem for the gastroenterologist. The clinician must attempt to distinguish between true organic disease, complications secondary to untreated eating disorder, and pure functional GI disorders. Symptoms may be very suggestive of organic disorders such as achalasia, celiac disease, eosinophilic gastroenteritis, inflammatory bowel disease or peptic ulcer, leading to extensive and confusing investigations to rule out these diagnoses (24–28). On the other hand, the GI symptoms may be complications of the underlying eating disorder arising from the impact of malnutrition and/or chronic emesis or laxative abuse. Patients with functional GI disorders such as irritable bowel syndrome or functional constipation also have many symptoms suggestive of an eating disorder (29). Although the patient with AN is often malnourished to the point that consideration of eating disorder is obvious, the patient with BN or BED may not be so easily recognized because of the secrecy of the symptoms and the absence of severe undernutrition (30). Many bulimic patients eat alone to conceal their binging habits and are unlikely to seek treatment unless encouraged. Some individuals self-identify as so-called pragmatic bulimics, that is, individuals who do not engage in bulimic behaviors frequently enough to consider themselves affected (8,31). GI symptoms can be difficult to treat and may interfere with the rehabilitation of these patients, especially patients with AN, in whom they may serve as a justification for food refusal.
Dysphagia and heartburn are common complaints in patients with AN and BN. Patients with emesis as a result of achalasia, esophageal inflammation, stricture, motility disorders, and gastroesophageal reflux disease can strongly resemble patients with bulimia and may require specific diagnostic evaluations and therapy (25,32,33).
In patients with repeated self-induced vomiting, frequent contact of the esophageal mucosa with regurgitated acidic gastric contents may cause esophageal inflammation and even dysplasia. Gastroesophageal reflux disease is an organic diagnosis regularly considered in the differential of these patients, however, a link between gastroesophageal reflux and BN remains unclear (33). Mallory-Weiss tears may occur (8,34). Kiss et al (35) performed upper GI endoscopy in 37 long-standing bulimic patients of mean age 24.3 ± 0.8 years and average duration of symptoms 61 ± 7 months. They found normal endoscopic appearance of stomach and esophagus in 23 patients. Eight patients had esophageal erythema, 2 had hiatus hernia, 6 had gastritis, 3 had duodenitis, and 1 had a gastric polyp. There are rare case reports of esophageal cancer, primarily adenocarcinoma, in young adults with bulimia, the youngest being 27 years old at diagnosis (33,36).
In most studies, esophageal motility is reported to be normal in BN and AN (32,37,38). Nickl et al (37) evaluated young adults with stable BN, and Benini et al (38) evaluated inpatients with AN exhibiting both binging/purging and restrictive disease activity. In both studies, esophageal complaints included dysphagia, heartburn, and regurgitation. Nickl's study evaluated esophageal motility in 12 young adults, 8 with BN and 4 with AN with bulimic features with a mean disease duration of 94 months comparing them with sex-matched controls. Esophageal motility was normal in all 24 subjects and controls despite reports of dysphagia and/or odynophagia in 1 control subject and 8 of the eating disorder patients (37). Benini et al also studied a younger group of hospitalized, malnourished inpatients during hospitalization and again after 22 weeks of nutritional rehabilitation, comparing them to age- and sex-matched controls. The inpatients with restrictive behaviors were younger (19.9 ± 0.7 vs 25.4 ± 1.1 years) and more malnourished (body mass index [BMI] 13.2 ± 0.6 vs 15.5 ± 0.7 kg/m2) than those with purging behaviors. Esophageal manometry was within the normal range in all patients except one with nutcracker esophagus. The resting lower esophageal sphincter pressures were higher in restricters than purgers (32.1 ± 4.6 vs 14.9 ± 2.2), but all values were within the normal range. Postdeglutitive peristalsis was normally propagated but was of significantly higher amplitude in the distal esophagus of patients compared with controls. In the majority of patients, both those with restrictive and binge-eating/purging behaviors, the esophageal complaints of dysphagia, heartburn, and/or regurgitation did not improve following nutritional rehabilitation (38).
There is a high prevalence of functional gastrointestinal disorders in patients with eating disorders. In 2015, Wang and colleagues (29) evaluated 100 women admitted for restrictive eating and/or purging behaviors using the Rome III classification of functional gastrointestinal disorders (39). One-third of the patients had functional esophageal complaints of at least 6 months duration, including heartburn in 22%, chest discomfort in 8%, and dysphagia in 6%. There are rare reports of oropharyngeal dysphagia with aspiration in severely malnourished patients with AN, presumably secondary to nutritionally mediated oropharyngeal muscle wasting (40).
A rare but serious esophageal complication of bulimia is esophageal rupture (Boerhaave syndrome). Patients may present with severe chest pain, painful swallowing, tachypnea, tachycardia, and pneumomediastinum. Early diagnosis is crucial. Surgery may be required, and without prompt attention, mortality is significant (41).
The practitioner should consider regular surveillance endoscopy in patients suspected of chronic purging behavior to identify those with persistent esophageal inflammation and (rarely) dysplasia. Routine monitoring of esophageal motility is not recommended in patients with well-documented bulimia. However, if the symptoms of a bulimic patient are atypical, e.g. persistent frequent emesis, nocturnal emesis, persistent cough, or emesis occurring in a public place, then evaluation for underlying organic disease, including esophageal motor disorders, should be considered (25,32). Addressing functional symptoms directly is important, as esophageal complaints often do not improve solely with weight recovery and nutritional rehabilitation (38).
Bloating, nausea, epigastric discomfort, and fullness are common complaints in AN and BN. The complaints may be a result of impaired gastric motility or may be purely functional (42). In Wang's study referenced above (29), functional gastroduodenal complaints included postprandial distress syndrome (45%), cyclic vomiting syndrome (17%), aerophagia/excessive belching (14%), nausea (10%), and rumination syndrome (7%).
Gastric emptying of solids is commonly delayed in patients with eating disorders, primarily in the setting of nutritional compromise (43–45). The literature is replete with evidence for gastroparesis in malnourished adults with AN (45–48). Studies in the pediatric population are limited and the evidence for gastroparesis is not conclusive. Diamanti et al (49) evaluated gastric myoelectrical activity with electrogastrography and gastric emptying with scintigraphy in 28 adolescent patients with eating disorders (18, AN; 10, BN) comparing results to healthy volunteers. They found a significantly higher rate of abnormal myoelectrical activity in patients with BN compared with AN and controls. The delay in gastric emptying was greater in BN than in AN patients. A more recent study by Perez et al (50) evaluated gastric emptying and accommodation using ultrasonography in 16 adolescents with AN compared with 22 controls. They found no differences in gastric emptying between AN and controls while gastric accommodation was significantly impaired in patients with AN. Complaints of upper GI dysfunction are common in patients with BN. The literature includes reports of impaired postprandial cholecystokinin release, altered satiety, increased gastric capacity, and diminished gastric relaxation in adults with BN (42,51,52). Although some studies describe delayed gastric emptying in BN, not all studies agree (32,47,48,53).
The mechanism of gastroparesis in individuals with AN and BN is not well understood and likely multifactorial. Smooth muscle atrophy may result from protein malnutrition. Metabolic and hormonal imbalance can develop as a result of poor nutrition, centrally mediated stress reactions, vomiting, or laxative abuse. Gastric dysrhythmia resulting from impaired autonomic function may produce antral hypomotility with delay in the grinding of solid food before transport into the duodenum (46,47,54).
The relation between nutritional rehabilitation, resolution of bulimic activity, and gastric emptying is variable. In some patients, nutritional rehabilitation and weight gain are associated with improved gastric emptying and stomach functioning (43,46,55). The threshold of nutritional deprivation at which gastroparesis begins and the level of renutrition required to initiate improvement are, however, not clear (56). Mechanisms postulated to improve gastric emptying in eating disorders may include the physical presence of food in the stomach, improved nutritional status, or rebalanced metabolic/hormonal mechanisms associated with nutritional and psychological gains (42,43,47,54). The clinician should consider the pros and cons of evaluating gastric emptying in patients with eating disorders as patient reported complaints have not been found to correlate well with the results of gastric emptying studies (47,54).
Bethanocol chloride, cisapride, domperidone, metoclopromide, and erythromycin all shorten gastric emptying time (55,57–60) and all have been used to treat eating disorder patients with presumed delay in gastric emptying. Adverse reactions, including cardiac arrhythmias and neurologic sequelae should be considered before prescribing these medications, particularly in AN where there is a risk of electrolyte imbalance and cardiac pathology (55,57–61). Nutritional rehabilitation is the safest and most efficacious therapy for gastroparesis in patients with AN. Intolerance of nutritional rehabilitation with dyspeptic symptoms may, however, hinder nutritional therapy. In a retrospective study, Rodriguez et al (62) noted improved symptoms in 55% of children treated with cyproheptadine for refractory upper GI complaints. The authors proposed that cyproheptadine diminished dyspeptic symptoms in part by increasing gastric accommodation. In light of the study by Perez et al (50), which noted impaired gastric accommodation in adolescents with AN, further study of the administration of cyproheptadine simultaneous with nutritional rehabilitation should be considered (62,63). Treating constipation in the eating disorder patient with gastric retention is essential as rectal distention may reflexively inhibit gastric emptying (54,64).
Delayed gastric emptying associated with eating disorders can have severe consequences. Gastric bezoars may accumulate (Fig. 1). Gastric dilation with or without bezoar may be severe enough to produce gastric necrosis and perforation (65). Gastric bezoar has been reported as a result of excessive ingestion of vegetables in a setting of delayed gastric emptying (65). Acute gastric outlet obstruction may be caused by gastric bezoar, superior mesenteric artery (SMA) syndrome, or duodenal ileus (66,67). Gastric smooth muscle atrophy and disturbances in gastric autonomic function may also lead to gastric distension (42). In some cases of severe gastric distension, intragastric pressure may eventually exceed gastric venous pressure, culminating in necrosis of the stomach wall (68). A high index of suspicion for acute gastric distension/gastric rupture is needed, particularly in patients after an episode of binge overeating. These patients may present initially with vague, mild abdominal pain, and gradual progressive abdominal distension. Emesis may not occur because of gastric atony. Ultimately, gastric necrosis with perforation, peritonitis, subcutaneous emphysema, and shock may ensue if the condition is untreated (69,70). Direct questioning of the patient about bulimic behaviors is critical. The diagnosis of gastric rupture can be confirmed with abdominal imaging or during emergent laparotomy. Treatment includes nasogastric tube decompression of the stomach, rehydration and correction of electrolyte disturbances. Occasionally, nasogastric decompression is not possible because of the presence of large retained food items, in which case endoscopic intervention or gastrostomy and surgical decompression may be necessary. A comprehensive evaluation of the patient is essential as systemic complications have included vascular compromise with lower extremity ischemia (66,71). The mortality rate of gastric perforation is reported to be as high as 60% to 80% (66,70).
SMALL AND LARGE INTESTINE
In Wang's study of functional GI complaints in inpatients with eating disorders, 53% were identified as having irritable bowel syndrome, functional bloating, or constipation. Anorectal complaints occurred in 16% (29).
Few studies have examined small bowel transit and motility in patients with eating disorders. Hirakawa et al (72) measured gastrocecal transit in malnourished patients and controls with AN using lactulose hydrogen breath test. Duodenocecal transit time was also examined in several of the patients with AN to assess the impact of gastroparesis on gastrocecal transit time. Transit time was significantly prolonged in patients with AN compared with controls (117 ± 31 vs 81 ± 33 minutes, P < 0.02) and the duodenocecal transit time in the 3 patients with AN tested was longer than the average orocecal transit time in healthy controls. In a similar study, Kamal and colleagues (73) observed a trend toward delay in the orocecal transit time in patients with AN (mean BMI 15.1 ± 2.2 kg/m2) and BN (mean BMI 22.9 ± 6.5 kg/m2) compared with controls that did not reach statistical significance. No studies currently available have evaluated small bowel peristalsis in these patients.
The impact of nutritional compromise on the GI tract has been extensively studied in animal models. In the setting of acute starvation, the small bowel responds with alteration of nutrient and ion transport, reduction in absorptive surface area with apoptosis and reduced cell proliferation and migration along the crypt-villus axis, and increased permeability to macromolecules. This scenario predisposes the host to nutrient malabsorption, bacterial translocation, and sepsis (74–77). Alternatively, the response of the small intestine to chronic malnutrition can be viewed as an adaptive response. Mucosal cell turnover and crypt to villous tip migration rate decrease. The ratio of villous cells to crypt cells increases, presumably increasing the absorptive capacity of the intestine. Human studies of AN support the proposition that the intestine in restrictive eating disorders has preserved absorptive capacity as does the gut in chronic undernutrition of other etiologies. Monteleone et al (78) examined intestinal permeability in a group of young women with AN comparing them with controls. Intestinal permeability was estimated by the lactulose (L) to mannitol (M) excretion ratio. Lactulose is absorbed paracellularly via intercellular tight junctions and mannitol is absorbed transcellularly. Both are excreted in the urine. In conditions with increased permeability, the L:M excretion ratio is increased because of relatively greater absorption of lactulose (79). The authors noted a reduced intestinal permeability in AN compared with controls, which may explain the low prevalence of sepsis in these patients (75,78). Martinez-Olmes et al (80) examined intestinal absorption in women admitted for AN and severe malnutrition at admission and after nutritional rehabilitation by d-xylose absorption test (81) and C-13 triglyceride breath test (82,83). Intestinal absorption was fully preserved throughout the study, including upon admission. Intestinal disaccharidases have not been examined in this population.
SMA syndrome is a complication of patients with AN who have experienced rapid weight loss. The loss of the normal mesenteric fat pad between the abdominal aorta and SMA results in entrapment of the third part of the duodenum between the SMA and aorta producing obstructive symptoms (84–86). SMA syndrome may present in an acute or chronic manner with food intolerance, postprandial abdominal pain and distension, vomiting which can be bilious, and weight loss. The pain is typically relieved by assuming the prone, knee-chest, or left lateral decubitus position, which relieves tension at the aortomesenteric angle (87). Diagnosis is confirmed with fluoroscopy or cross-sectional imaging (84). Figure 2 displays fluoroscopic evidence of abrupt cessation of flow of contrast before the third portion of the duodenum in an adolescent with SMA syndrome. Computerized tomography and magnetic resonance studies provide a measure of the angle and distance between aorta and SMA. The normal range for the aortomesenteric angle is 38 to 65 degrees. The normal range for aortomesenteric distance is 10 to 28 mm. An aortomesenteric angle <22 to 25 degrees and aortomesenteric distance <8 mm correlate well with the occurrence of SMA syndrome (85–87). Postpyloric enteral feeding promotes restoration of the retroperitoneal fat and leads to resolution of symptoms in most cases (88). A review of reported cases of SMA syndrome in eating disorders (66) found that 73% of cases responded to conservative therapy whereas 29% required surgical intervention.
Many factors contribute to the development of constipation in patients with eating disorders. Malnutrition causes smooth muscle atrophy and electrolyte abnormalities, especially hypokalemia. Malnourished patients are at risk for low triiodothyronine (T3) sick euthyroid syndrome (89). Purging by emesis or laxative abuse can induce hypokalemia (90). Antidepressants, particularly tricyclic antidepressants, may delay intestinal transit (91). Colon transit studies have demonstrated delayed colonic transit in the majority of malnourished AN inpatients. Kamal et al (73) reported delayed whole gut transit in AN patients versus controls (66.6 ± 29.6 vs 38 ± 19.6 hours). Chun and colleagues (94) reported whole gut transit time of 86.6 ± 17.8 hours in AN vs 28 ± 8.6 hours in controls. Chiaroni and colleagues (95) reported delayed transit in 8 of 12 AN patients. In the majority of the patients studied pre- and postnutritional therapy, the colonic transit times normalized. Many patients still, however, complained of a subjective sensation of constipation (94,95). Kamal et al (73) also reported that whole gut transit time was delayed in patients with BN compared to controls despite their normal BMI.
Studies of anorectal manometry in patients with AN have shown consistent differences compared with controls. Chiarioni et al (95) found that 42% of patients exhibited pelvic floor dysfunction with inability to expel a rectal balloon versus none in the control group. Mean resting external anal sphincter pressure is significantly reduced in AN versus controls (50.6 ± 19 vs 83.1 ± 24.4 mmHg). Threshold for the urge to defecate is higher in AN than controls (121 ± 86.5 vs 58.3 ± 19.5 mL). After refeeding, colonic transit normalized, but anorectal manometry remained abnormal, suggesting a persistent anorectal and pelvic floor dysfunction. Rarely, rectal prolapse with full-thickness protrusion of the rectal wall through the anal canal occurs in patients with AN and may necessitate surgical correction (66).
Patients with eating disorders use laxatives not only to relieve the symptoms of constipation and abdominal fullness, but also in an attempt to promote weight loss and “purification” through the expulsion of stool (96). The loss of weight after laxative use is almost entirely a result of water loss, not nutrient malabsorption. Nutrient malabsorption estimated by bomb calorimetry during laxative use has been estimated by one source at approximately 12% (92).
Laxatives should be used sparingly for constipation in patients with an eating disorder because of the potential for abuse. Evidence for the efficacy of laxatives during nutritional rehabilitation in patients with AN is sparce. The literature suggests that nutritional rehabilitation is effective in improving GI transit in most individuals. Unfortunately, however, despite improvement in BMI and whole intestinal transit, most patients with AN continue to complain of a sensation of constipation (73,94,95).
The prevalence of laxative abuse in patients with BN and AN has been reported to be as high as 75% (93,97,98). The abuse is often concealed by the patient, making true estimates difficult to obtain. Excessive use of most stimulant laxatives is associated with electrolyte and acid-base imbalance. Potassium is the primary electrolyte in stool water (70–90 mmol/L), with lower concentrations of sodium and chloride (93). Hypokalemia can induce muscle, renal, and cardiac injury (93,99). Hypermagnesemia with neuromuscular injury can occur with magnesium containing laxative abuse (100). Laxative abuse can trigger secondary hyperaldosteronism in response to chronic dehydration. Acute cessation of laxative intake can thus precipitate severe water and sodium retention with consequent cardiac and pulmonary fluid overload (93).
The morbidities associated with laxative abuse have changed over time as the active ingredients have been modified. In the past, concerns were raised about the ingredients in commonly used stimulant laxatives, including diphenylmethane derivatives (bisacodyl), castor oil, and anthraquinones (senna and cascara). The mode of action of stimulant laxatives is to alter fluid and electrolyte transport and/or motility in the intestines. Concern was raised about development of cathartic colon with overuse of these laxatives. Cathartic colon presented as severe colonic inertia associated with loss of colonic myenteric neurons, atrophy of smooth muscle, loss of haustrations, decreased volume and numbers of interstitial cells of Cajal, and loss of enteric neurons (101–104). It is currently believed that cathartic colon is most likely related to undefined toxic compounds previously present in laxatives, including the neurotoxin podophyllum (105–107), or an underlying undiagnosed motility disorder involving the myenteric plexus (93,107–109). Furthermore, phenolphthalein was the active ingredient in many over-the-counter laxatives. In 1997, the US Food and Drug Administration banned the use of phenolphthalein, as studies in animals exposed to high doses revealed an association with cancer and with genetic mutations in gametes (107,110,111).
Currently, the only significant pathologic entity associated with laxatives is mucosal damage induced by castor oil and anthranoid derivatives. Castor oil can injure intestinal epithelial cells (112). Anthraquinone-derived laxatives, when used chronically, can induce a reversible melanosis coli and gastric melanosis, a brownish pigmentation easily observed on endoscopy and colonoscopy (113). Melanosis coli (Figs. 3 and 4) results from the accumulation of lipofuscin in the macrophages of the lamina propria during cellular apoptosis (103). The finding appears to be benign with no evidence for genetic or malignant potential (114–116). The retained pigment does not extend to the muscle layers or the enteric plexuses, and it is thought to lessen and disappear when the offending agent is removed (103).
Necrotizing colitis is a rare complication in patients with severe malnutrition from AN. A very high index of suspicion is required to make this diagnosis. The initial complaint is usually abdominal pain early in refeeding therapy (117). Necrotizing colitis has been reported to develop even when refeeding is introduced cautiously. Patients may have diminished bowel sounds, abdominal distension and tenderness, hematochezia, and apparent delayed gastric emptying with emesis and gastric residuals. Later, radiologic findings include pneumatosis intestinalis involving small and large bowel, portal venous air and pneumoperitoneum. Intestinal dilatation and bowel wall thickening occur. The pathogenesis of necrotizing colitis in AN is thought to be similar to that of infant necrotizing enterocolitis. Proposed risk factors include starvation-induced intestinal hypoperfusion with hypoxic-ischemic bowel injury, intestinal dysmotility, and compromised intestinal mucosal integrity. Alterations to the intestinal microbiome and bacterial translocation have not been evaluated as possible causes in AN (117).
Noninflammatory fibrotic injury to the pancreas has been observed in humans and in animals with protein-calorie malnutrition. Pancreatic histology in these cases reveals acinar cell atrophy, disorganization of the acinar pattern, stellate cell activation, reduction in the number of zymogen granules, and fibrosis of variable severity, which can involve the entire pancreas. Damage to all pancreatic organelles is seen in children dying of protein calorie malnutrition (118,119). Duodenal aspirates of severely malnourished children exhibit functional pancreatic compromise with reduced amylase, lipase, and trypsin levels. The secretion of bicarbonate and water is usually normal as ductular function is usually preserved (120). In the majority of reported cases, pancreatic exocrine dysfunction resolves with nutritional rehabilitation (119,120). Martinez-Olmos et al (80) measured pancreatic exocrine function in a small group of chronically malnourished AN patients using 2 noninvasive tests of pancreatic function, 13C-labeled triglyceride breath test (82,83) and fecal elastase (121,122). The 13C-labeled triglyceride breath test assesses lipase activity and fecal elastase 1 is a general measure of pancreatic exocrine function. Fecal elastase is not affected by GI motility or small bowel malabsorption (121,122). The authors’ normal findings in these women contrasts with the abnormalities noted in other studies of malnourished patients and may relate to the small size of the study or to the relative lack of sensitivity of the study tests they used to detect mild pancreatic insufficiency (80,83,121–123).
Acute pancreatitis has been reported in patients with AN. Proposed mechanisms include malnutrition related microlithiasis, ischemia, and/or structural damage. Ischemic injury to the pancreas may occur with fluid shifts and cardiac compromise during nutritional rehabilitation. Duodenal dysmotility may promote retrograde flow of duodenal contents into the pancreatic duct, initiating an inflammatory cascade, and pancreatic autolysis (124). Serum amylase levels can be elevated in patients with BN, but this is more commonly of salivary, not pancreatic, origin. Serum lipase and pancreatic isoamylase levels are more sensitive and specific indicators of pancreatitis in patients with an eating disorder (66,125).
Hepatic injury occurs in both BN and AN. In obese individuals with binging, nonalcoholic fatty liver disease has been seen (126). In patients with malnutrition, liver injury ranging from asymptomatic elevation of hepatic transaminases to hepatic failure has occurred both during the malnourished state and upon nutritional rehabilitation. In 1 study of patients presenting to an eating disorder clinic, approximately 4% had elevated hepatic transaminases. Many of the subjects in this study, however, had comorbidities that may have contributed to the elevated transaminases (127). In another study of patients hospitalized for AN, more than one-third had elevated hepatic transaminases (128). Although abnormal transaminases in most malnourished patients normalize with nutritional rehabilitation, hepatitis, and acute fatty liver can develop during refeeding and rarely progress to hepatic failure.
The severity of malnutrition is a strong predictor of the risk of liver injury in patients hospitalized with AN (129). In AN, liver injury often occurs as a result of starvation-induced autophagy. Autophagy is a normal homeostatic cell process, which in health allows for recycling damaged or aged cell components. The phagophore consumes a portion of the cytoplasm including aging organelles to form an autophagosome. Fusion of a lysosome with the autophagosome creates an autolysosome. Material in the autolysosome is degraded by lysosomal hydrolases and the breakdown products are released into the cytoplasm (130,131). Malnutrition in AN causes a compensatory augmentation of autophagy to promote nutrient preservation and protect hepatocytes. When starvation is severe and chronic (BMI ≤ 13 kg/m2), excessive activation of autophagy can lead to hepatocyte cell death and liver insufficiency (130). This form of acute liver insufficiency is unique in that the liver does not exhibit necrosis or apoptosis but instead, electron microscopy reveals numerous autophagosomes with reduction of organelles and glycogen (130,132). In some patients with AN, the liver may incur hypoxic injury as a result of low cardiac output and hepatic hypoperfusion. Decreased cardiac output may occur as a result of cardiac muscle atrophy and electrolyte-induced arrhythmias and may be exacerbated during refeeding syndrome (133).
Eating disorders, including AN and BN, can present with a wide range of oral, salivary, and GI manifestations. The clinician must determine whether the complaints are organic in and of themselves, whether they represent complications of the eating disorder, or whether they are primarily functional. It is often the case that the complaints represent a combination of these 3. The secrecy enshrouding symptoms experienced by patients with eating disorders is a major problem that often prevents obtaining a reliable history. Diagnostic evaluations should be carefully selected and testing should not delay the introduction of nutritional therapy when an eating disorder is suspected as the oral, salivary, and GI complications are often reversible with nutritional rehabilitation.
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