Medical complications of bulimia nervosa

A SERIOUS MENTAL ILLNESS WITH PHYSICAL CONSEQUENCES

Bulimia nervosa (BN) is a serious mental illness characterized by binge-eating followed by compensatory purging behaviors. It is frequently accompanied by medical sequelae that affect normal physiologic functioning and contribute to increased morbidity and mortality rates.¹ Most people with BN are of normal weight or even overweight,² and are otherwise often able to avoid detection of their eating disorder. Thus, it is important that clinicians familiarize themselves with these complications and how to identify patients with disordered eating patterns.

ONSET IN ADOLESCENCE, AND FAIRLY COMMON

BN typically develops in adolescence or young adulthood and affects both sexes, although it is much more common in girls and young women.⁶ It affects people regardless of sexual orientation but has been shown to be more prevalent in nonheterosexual males.⁷ Studies have found similar prevalence of BN among different racial and ethnic groups. Individuals with BN are generally within or above the normal weight range.²

According to pooled data from the World Health Organization, the lifetime prevalence of BN in adults is 1.0% using the older DSM-IV criteria,⁷ which is greater than the reported prevalence of anorexia nervosa. Prevalence estimates are higher with the broadened DSM-5 criteria, ranging from 4% to 6.7%.⁸

There are multiple predisposing and perpetuating factors—genetic, environmental, psychosocial, neurobiological, and temperamental. These can include impulsivity, developmental transitions such as puberty, internalization of the thin ideal, and weight and shape concerns.⁹ A history of childhood trauma, including sexual, physical or emotional trauma, has also been associated with BN.¹⁰

More than 70% of people with eating disorders report concomitant psychiatric comorbidity—affective disorders, anxiety, substance use, and personality disorders are most common in BN.¹¹ Psychiatric comorbidities as well as hopelessness, shame, and impulsivity associated with the illness may contribute to challenges with nonsuicidal self-harm, suicidal ideation, and death by suicide. Individuals with BN experience lifetime rates of nonsuicidal self-harm of 33% and are nearly 8 times more likely to die by suicide than the general population.^12,13 The reported standardized mortality rates in those with BN are less than in those with anorexia nervosa but are still significantly elevated at 1.5% to 2.5%.¹

MEDICAL COMPLICATIONS

As noted earlier, BN is associated with a significantly increased mortality rate even though many of these patients are young. Much of this elevated mortality is attributable to the medical complications associated with BN, which are a direct result of the mode and frequency of purging behaviors. Thus, for example, if someone uses laxatives 3 times per day or vomits 1 time per day, there may be no medical complications, but many patients engage in their respective purging behaviors many times per day, leading to multiple complications.

Aside from the electrolyte aberrations from purging, some of the medical complications are unique to the mode of purging. Furthermore, BN has been found to increase the risk of any cardiovascular disease, including ischemic heart disease and death in females.¹⁴ These same complications may also apply to patients with anorexia nervosa of the binge-purge subtype in contrast to those patients with anorexia nervosa who only restrict caloric intake but do not purge.

We will now discuss, in a systems-based approach, the medical complications that develop in people with BN as a direct result of their purging behaviors.

Skin

Russell sign (Figure 1), named after Dr. Gerald Russell, who first defined the disease BN in 1979, refers to the development of calluses on the dorsal aspect of the dominant hand.¹⁵ It is pathognomonic for self-induced vomiting and is due to traumatic irritation of the hand by the teeth, from repeated insertion of the hand into the mouth to provoke vomiting.¹⁵

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Figure 1

The Russell sign.

Russell sign is not commonly seen since many of these patients are able to spontaneously vomit or they utilize utensils to initiate self-induced vomiting.

Parotid glands

Parotid gland hypertrophy, or sialadenosis (Figure 2), may develop in more than 50% of people engaging in purging via self-induced vomiting.¹⁷ Ironically, it usually develops 3 to 4 days after cessation of purging. Symptoms include bilateral painless enlargement of the parotid glands and, occasionally, other salivary glands. It is believed to develop due to either cholinergic stimulation of the glands, hypertrophy of the glands to help meet demands of increased saliva production, or excessive backup of saliva that is no longer needed with cessation of vomiting.

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Figure 2

Sialadenosis.

Pathology study reveals hypertrophied acinar cells with otherwise preserved architecture without evidence of inflammation.

Swelling may subside with cessation of purging; failure of the parotid gland hypertrophy to resolve is highly suggestive of ongoing purging.¹⁸ Sialadenosis also tends to resolve with the use of sialagogues such as tart candies. Heating pads and nonsteroidal anti-inflammatory drugs also have a therapeutic role and perhaps should be prophylactically initiated in those with a long history of excessive vomiting who engage in treatment to stop purging. In rare refractory cases, pilocarpine may be judiciously used to reduce the glands back to normal size.¹⁹

METABOLIC AND ELECTROLYTE DISTURBANCES

In addition to the above body system complications from purging, each of the common methods of purging used by patients with BN can be associated with specific electrolyte disturbances. These electrolyte abnormalities are likely the most proximate cause of death in patients with BN. When a patient simultaneously engages in multiple modes of purging behaviors, just as their level of psychiatric illness can be more profound, so too the electrolyte disturbance profiles can overlap and be more extreme.

Patients with a history of a known purging behavior should be screened at increased frequency for serum electrolyte disturbances, up to even daily, depending on the frequency of their purging behaviors.³¹ In a study of patients admitted to inpatient and residential eating disorder treatment without prior medical stabilization, 26.2% of the BN patients presented with hypokalemia (potassium < 3.6 mmol/L) on their admission laboratory testing, while 8.5% had hyponatremia (sodium < 135 mmol/L) and 23.4% had a metabolic alkalosis (bicarbonate > 28 mmol/L).³²

Self-induced vomiting is the most common method of purging in BN.³³ Patients with self-induced vomiting or diuretic abuse, or both, have been shown to present with hypokalemia, hypochloremia, and a metabolic alkalosis.³⁴ The severity of the electrolyte abnormalities worsens with the frequency of vomiting.

Similarly, laxative abuse also results in hypokalemia and hypochloremia. However, either a non-anion gap metabolic acidosis or a metabolic alkalosis may be present, depending on the chronicity of the laxative abuse.³⁵ Generally, more chronic diarrhea results in a metabolic alkalosis. Hyponatremia can also be present with these 3 purging behaviors. The hyponatremia encountered is most often of the hypovolemic type due to chronic fluid depletion as a result of the purging behaviors.

PSEUDO-BARTTER SYNDROME

The aforementioned process of renin-angiotensin-aldosterone system activation results in what has been termed pseudo-Bartter syndrome due to resulting serum and histochemical findings on renal biopsy that resemble Bartter syndrome.³⁶ However, the findings are not due to intrinsic renal pathology but rather are a result of the chronic state of dehydration from the purging behaviors. The resultant elevation in serum aldosterone, an integral part of pseudo-Bartter syndrome, can result in rapid edema formation when the purging behaviors are abruptly stopped. The reason is that the serum aldosterone levels remain high, causing salt and water retention even though the patient is no longer losing fluid, as the purging has ceased.

EVALUATION AND MANAGEMENT OF ELECTROLYTE DISTURBANCES AND PSEUDO-BARTTER SYNDROME

Covert purging should be strongly suspected in otherwise healthy young women presenting with hypokalemia without an alternative medical cause.³⁷ However, hypokalemia alone is not specific for underlying purging behaviors.³⁴

If the patient is not forthcoming about their behavior when confronted, a spot urine potassium, creatinine, sodium, and chloride measurement can be obtained to further assess the source of potassium loss. A urine potassium-to-creatinine ratio less than 13 can identify hypokalemia resulting from gastrointestinal loss, diuretics, poor intake, or transcellular shifts. A urine sodium-to-chloride ratio can also be calculated. Vomiting is associated with a urine sodium-to-chloride ratio greater than 1.6 in the setting of hypokalemia, whereas laxative abuse is associated with a ratio less than 0.7.³⁶

Chronic hypokalemia is often asymptomatic and can be corrected slowly. If the serum potassium level is no lower than 2.5 mmol/L and the patient has no physical symptoms or electrocardiographic changes of hypokalemia, the hypokalemia can be managed by stopping the purging behavior and giving oral potassium supplementation.^38,39 Adherence to oral potassium repletion can be improved by using potassium chloride tablets rather than liquid preparations.³⁸ Aggressive intravenous potassium supplementation places patients at risk of hyperkalemia and should be reserved for more critically low serum potassium levels.

Severe hypokalemia (serum potassium less than 2.5 mmol/L) requires both oral and intravenous repletion of potassium. This repletion process is aided by giving isotonic saline with potassium chloride intravenously at a low infusion rate (50–75 mL/hour). Correcting the patient’s volume depletion is required to correct the metabolic alkalosis and interrupt renin-angiotensin-aldosterone system activation. Untreated severe hypokalemia can result in a prolonged corrected QT interval on electrocardiography, subsequent torsades de pointes, and other life-threatening cardiac arrhythmias. Simply attempting to replete potassium without attention to the concomitant metabolic alkalosis will be unsuccessful because of the ongoing kaliuresis due to aldosterone’s ongoing effects on the kidneys. Rarely, chronic hypokalemia has been associated with acute renal failure, with renal biopsy demonstrating interstitial nephritis, termed hypokalemic nephropathy.⁴⁰

Mild hyponatremia often will autocorrect with interruption of purging behaviors and oral rehydration. However, if the serum sodium is less than 125 mmol/L, hospitalization is warranted for close monitoring and for slow correction with isotonic saline—ie, at a rate that increases the serum sodium by no more than 4 to 6 mmol/L every 24 hours. This avoids the serious complication known as central pontine myelinolysis.⁴¹ If hyponatremia is severe (serum sodium < 118 mmol/L), the patient will likely benefit from admission to an intensive care unit and renal consultation for consideration of administration of desmopressin to prevent overcorrection.

Metabolic alkalosis can develop in patients with BN as a result of decreased intravascular volume, elevated aldosterone, and hypokalemia; it is most often saline-responsive. A spot urine chloride can be used to inform care. If it is less than 10 mmol/L, the metabolic alkalosis is hypovolemic and will improve with slow intravenous saline administration. Clinicians may also rely on physical examination to help determine the patient’s volume status.

Due to the underlying risk of pseudo-Bartter syndrome in patients with BN who abruptly stop purging, care should be taken to avoid aggressive fluid resuscitation. Interruption of purging behaviors in conjunction with rapid intravenous fluid resuscitation can result in marked and rapid edema formation and weight gain, which can be psychologically distressing. Thus, low infusion rates of saline (50 mL/hour) and low doses of spironolactone (50–100 mg initially with a maximum of 200–400 mg/day) should be initiated and titrated based on edema and weight trends to mitigate edema formation.⁴² Spironolactone is generally continued for 2 to 4 weeks and then should be tapered by 50 mg every few days thereafter. Occasionally, in extreme laxative abusers, proclivity toward edema may persist and necessitate an even slower spironolactone taper.

MEDICAL COMPLICATIONS OF BINGE-EATING

The literature on complications of binge-eating specific to BN is limited, and thus, we must look to studies of binge-eating disorder. However, patients with binge-eating disorder tend to be overweight or obese, as they do not purge after binge episodes. Thus, many of the medical complications in binge-eating disorder, such as type 2 diabetes, hypertension, nonalcoholic fatty liver disease, and metabolic syndrome are obesity-related.⁴³

In contrast, many patients with BN have a normal body mass index. Therefore, it is difficult to infer that the medical complications that occur in binge-eating disorder are the same as those that occur from binge-eating in BN. However, the extrapolation does make sense in some instances. For instance, patients who binge are at higher risk of nutritional deficiencies because food taken in during a binge tends to be processed, high in fat and carbohydrates, and low in protein. A diet low in vitamins, including A and C, and minerals increases the risk of nutritional deficiencies. Additionally, patients with binge-eating disorder have more gastrointestinal complaints such as acid reflux, dysphagia, and bloating, which, as outlined above, are also seen in BN. Thus, bingeing may play a role in these symptoms.

Lastly, gastric perforation has been reported in patients with BN in the context of a bingeing episode marked by excessive stomach distention, resulting in gastric necrosis.⁴⁴ Furthermore, gastric outlet obstruction has also been reported in this patient population due to formation of a food bezoar.

IDENTIFICATION AND MENTAL HEALTH TREATMENT

The Eating Disorder Screen for Primary Care has been shown to effectively screen patients for disordered eating in a general medicine setting.⁴⁵ It consists of 5 questions:

• Are you satisfied with your eating pattern? (“No” is considered an abnormal response.)

• Do you ever eat in secret? (“Yes” is an abnormal response to this and the remaining questions.)

• Does your weight affect the way you feel about yourself?

• Have any members of your family suffered from an eating disorder?

• Do you currently suffer with or have you ever suffered in the past with an eating disorder?

Cotton et al⁴⁵ found that an abnormal response to 2 or more of these questions had a sensitivity of 100% and a specificity of 71% for eating disorders.

Standard mental health treatments for BN include nutritional stabilization and behavior interruption, monitoring for and appropriate management of associated medical complications, prescribing medications as clinically indicated, and psychotherapeutic interventions. Cognitive behavioral therapy is the recommended initial intervention for the treatment of BN. A recent network meta-analysis suggested that guided cognitive behavioral self-help and a specific form of cognitive behavioral therapy—individual cognitive behavioral therapy for eating disorders—may most likely lead to full remission.⁴⁶

No drug has been developed specifically for the treatment of BN (Table 2). Fluoxetine, with a target dose of 60 mg daily independent of the presence of comorbidities, is the only medication approved by the US Food and Drug Administration for BN. This selective serotonin reuptake inhibitor has been shown to reduce the frequency of binge-eating and purging episodes significantly, more so than fluoxetine 20 mg daily and placebo.⁴⁷ Fluoxetine is recommended for patients who do not respond adequately to psychotherapeutic interventions.⁴⁸

Other selective serotonin reuptake inhibitor antidepressants along with the anti-epileptic topiramate also have been shown to have modest efficacy.⁴⁹ Bupropion, which has a boxed warning and is contraindicated in the treatment of BN, should not be used due to an increased risk of seizure.

No clinical trials have evaluated the use of stimulant medications in the treatment of BN. Often, stimulant medications are discontinued in patients until there is a period of abstinence from purging behaviors. Following abstinence, reinitiation of the stimulant could be reconsidered off-label if bingeing behaviors persist or attention deficit hyperactivity disorder is a comorbidity, or both. There can be some utility to reinitiation with a clear treatment agreement outlining expectations for maintaining efforts at purging symptom interruption and continued stimulant prescribing.

In general, concomitant treatment for anxiety or depression should be pursued if these co-occur with BN. Selective serotonin reuptake inhibitors such as fluoxetine would also target these symptoms. If a trial of fluoxetine has failed, then sertraline or escitalopram would be reasonable second-line options. Typically, citalopram would not be used due to higher risk of prolonged QT interval than other selective serotonin reuptake inhibitors, especially given the possibility of electrolyte abnormalities in BN. Paroxetine would not be used due to the potential for weight gain as a side effect.

PROGNOSIS

Increased risk of relapse has been associated with greater psychosocial dysfunction and body image disturbance.⁵⁰ In patients requiring hospitalization, a number of factors have been shown to predict poor outcome, including fewer follow-up years, increased drive for thinness, older age at initial treatment, and more impairment in global functioning.⁵⁰ Recovery is possible with variable remission rates, based on the type of study and definition of remission, from 38% and 42% at 11-and 21-year follow-up, respectively, and 65% of individuals at a 9-year and 22-year follow-up.^50,51 This reinforces the need to utilize accessible and effective treatments to achieve sustained recovery.

INITIAL CASE CONTINUED

You release the patient in the initial clinical scenario from her follow-up appointment without intervention or follow-up laboratory testing. You fail to recognize the Russell sign, and you advise her that the edema is due to fluids administered in the emergency department and will self-resolve. She returns to her purging behaviors with increased vigor due to perceived weight gain from the edema.

One month later, she experiences a syncopal episode during cross-country practice, again necessitating oral potassium and intravenous saline administration. On follow-up, her edema is worse, and you recognize the Russell sign, having just read this review article. On follow-up laboratory testing, you note ongoing mild hypokalemia and screen her for an eating disorder. The screening is positive, and she discloses to you not only about her daily self-induced vomiting, but also her abuse of stimulant laxatives and bingeing episodes.

You initiate a referral to a residential treatment facility for eating disorders, start her on daily potassium chloride 40 mmol, and plan for weekly follow-up laboratory testing until she enters residential treatment.