66 - 80: Multiple Comorbidities in People with Eating Disorders

Eating disorders, including anorexia nervosa and bulimia nervosa, are complex psychiatric diseases characterized by severe disturbances in eating behavior often resulting in dramatic consequences for the physical health of patients. Anorexia nervosa is characterized by restricted eating, obsessive fears of being fat and the voluntary pursuit of thinness with an inability to maintain a normal healthy body weight. Despite increasing emaciation and a body weight below 85% of the ideal, individuals with anorexia are dissatisfied with the perceived size and shape of their body, and engage in unhealthy behaviors to perpetuate weight loss or prevent weight gain. There are two subtypes of anorexia nervosa: anorexia nervosa binge-eating/purging subtype, where patients engage in binge-eating/purging behaviors, and anorexia nervosa restricting subtype, where patients exclusively restrict their food intake.

Bulimia nervosa is characterized by recurrent episodes of uncontrolled binge eating coupled with inappropriate compensatory behaviors, such as vomiting, laxative abuse, food restriction and/or excessive exercising, in order to prevent weight gain due to the patient's pathological fear of becoming fat. Generally, because of the ingestion of some food in the course of bingeing, people with bulimia nervosa have a normal body weight.

Anorexia and bulimia are perhaps the most intriguing combinations of psychological and physical pathology. Even though appearing after the beginning of an eating disorder and therefore not representing their primary cause, physical comorbidity plays an important role in the development of psychopathology, its course and prognosis, possibly through the essential contribution that nutritional alterations typical of these diseases exert on the brain biochemical function. The physical complications observed in eating disorders have been considered a consequence of nutritional derangements because of the similarities with the alterations observed in simple starvation. People with bulimia are not starving, but the loss of food from vomiting or use of laxatives, the biased selection of macro-/micronutrients typical of the bingeing episodes, and the alternation of gorging and severe dieting might lead to malnutrition, resulting in some of the adverse effects of simple starvation. What remain uncertain are the mechanisms by which starvation during anorexia and malnutrition with bulimia induces and maintains the physical complications of the syndromes. In particular, it is unclear why some patients show the full spectrum of physical complications while others with a very similar psychopathological picture do not. Moreover, it is not clear what influence is exerted by peripheral physical complications on the course, response to treatments and prognosis of eating disorders. These problems must be addressed in the future.

This chapter provides a brief review of the most common physical complications occurring in patients with eating disorders [1,2,3,4,5] (table 1).

In both subtypes of anorexia nervosa, cutaneous alterations occur as a consequence of starvation, self-induced vomiting and abuse of purging drugs [6,7].

Brittle hair and eyelashes and loss of hair and eyebrows are present in people with both subtypes of anorexia nervosa, while the skin is often covered by a fine, down-like hair known as ‘lanugo', growing especially on the face, superior lip, back, arms and legs. Fragile nails and a dystrophic aspect of the skin, which is dry and scaling, pale or yellowish like old paper or brownish like dirt because of cornification, occur because of nutritional deficiencies and starvation-linked hypothyroidism that develops early in the disease. The yellowish color of the skin is partly due to the hypercarotenemia, which is typically observed in people with anorexia in contrast to involuntary starvation when hypocarotenemia is characteristic. In people with anorexia, the phenomenon is linked to the excessive consumption of carrots, pumpkins and similar yellowish vegetables, but possibly also to an acquired defect in the absorption, use or metabolism of carotene. Skin thickness and median collagen content are significantly reduced. Spontaneous cuts are frequently observed at the corners of the lips and near the nails.

The presence of skin trauma and calluses on the dorsal surface of hands, secondary to using the hands as an instrument to induce vomiting, is characteristic and was first described in 1979 by Russell (Russell sign) [7]. The lesions appear in people with anorexia nervosa binge-eating/purging subtype, and can be anywhere on the dorsum of the hand, but more frequently at the metacarpophalangeal joint of each finger. They rapidly progress to hyperpigmentation of the calluses and scarring. It has been reported that these lesions may disappear in the later course of the disease, as many patients train themselves to vomit reflexively. Poor wound healing is frequent. Facial dermatitis, seborrheic dermatitis and acne are occasionally observed.

Peripheral edema, especially pretibial, may occur in 20% of people with anorexia mostly of the restrictive subtype, often during the refeeding phase. A mild form may occur in people with the restrictive subtype of anorexia without a clear etiological cause in those with normal plasma proteins, and in particular albumin levels. A more severe form is associated with purging and chronic laxative abuse, which leads to marked hypoproteinemia and subsequent lowering of plasma osmotic pressure and passage of fluids from the vascular tree into tissues. This severe form of edema is rapid in onset and may lead to life-threatening shock, renal infarction and cardiovascular collapse due to an inability to maintain fluid volume [1].

In people with the binging subtype of anorexia, vomiting strain may lead to the appearance of cutaneous petechiae, especially on the face, and hemorrhage of the conjunctiva, possibly linked to fragility of venous and capillary walls, reduced platelet number and increased capillary vessel permeability. With repeated vomiting, subcutaneous emphysema of the neck has been described, in some cases associated with spontaneous pneumomediastinum.

Stable erythema, linked to the abuse of phenolphthalein-containing laxatives or ipecac, has been reported in people with anorexia. Cutaneous alterations linked to vitamin deficiency, including scurvy or pellagra, have been infrequently reported. More frequent are signs of self-injury, such as excoriated acne and erythema ab igne.

In bulimia, lesions of the skin, hair and other annexes are similar to those observed in anorexia, only occurring less frequently [8]. The most frequent alteration is the Russell sign, which is due to self-induced vomiting. Peripheral edema may be seen although less frequently than in anorexia, possibly due to the loss of electrolytes through vomiting and the relative poor consumption of proteins in these patients. Subcutaneous emphysema may be present secondary to recurrent severe vomiting strain. Signs of self-injury are frequent.

Dental caries is frequent in anorexia, being related to starvation in the restricting type and to both vomiting and excessive carbohydrate intake in the bingeing-purging type [9]. There is delayed formation and missing tooth enamel, as well as erosion (perimolysis) of the maxillary lingual surfaces, especially of the anterior teeth. A frequent oral pathology is angular cheilosis, a stomatitis characterized by pallor and maceration of the mucosa at the corners of the mouth, which may result in painful linear fissures and consequent scars. It is mostly observed in the binging subtype of anorexia, and is caused by the caustic effect of regurgitated gastric acid content, but may also be an expression of an underlying vitamin deficiency, especially of riboflavin (B₂) and pyridoxine (B₆) - in this case being seen also in the restrictive subtype of anorexia.

Gingival health is impaired in anorexia, possibly due to the chronic irritation produced by the regurgitated gastric acid content, often associated with painful pharyngeal erythema. Hypertrophy of the salivary glands (sialadenosis) is common in the binging subtype of anorexia, again linked to repeated vomiting, with occlusion of the salivary ducts by fragments of nondigested food. Generally the hypertrophy is painless, mostly bilateral, and more frequent in the parotids, which may enlarge up to five times their normal size. The hypertrophy of the glands may be more evident in the case of concomitant masseteric hypertrophy, especially present in people with the binging subtype of anorexia affected by bruxism [10].

The oral alterations reported for the binging subtype of anorexia are also present in bulimia nervosa [10]. Most of the dental problems are related to the frequent vomiting resulting in enamel injury and dental caries, which may also be induced by the ingestion of large amounts of carbohydrates. Enamel biopsies (postmortem) reveal a preserved thickness of the surface, with normal hardness measurements suggesting that oral hygiene and use of fluoride may minimize the erosive effect of vomiting on tooth enamel. Sialadenitis is extremely frequent in bulimia, and is often related to hyperamylasemia. The phenomenon has been attributed to excessive food intake and a reflex stimulation of the glands during vomiting.

The esophagus is frequently affected in both types of anorexia nervosa. Pathologies include stenosis, esophagitis (which causes epigastric or substernal burning pain radiating to the jaw or down both arms), erosions and ulcers of the gastroesophageal junction and esophageal rupture. These lesions are due mostly to vomiting, the frequently spastic motility of the esophagus and a neuropathy linked to vitamin deficiencies. Superior mesenteric artery syndrome occurs frequently in anorexia [11].

In the restrictive type of anorexia, gastric volume is normal or reduced, the wall's smooth muscle is atrophic and atonic, and antral mobility is abnormally low; gastric emptying is always slow and delayed for solid food and hypertonic liquids [11]. These abnormalities are partly responsible for the postprandial early feeling of gastric fullness and the very frequent belching observed in people with anorexia. Complications secondary to binging in the bulimic type of anorexia include gastric dilatation, which is rarely associated with rupture.

During refeeding, gastric bloating and other nonspecific abdominal discomforts usually persist. Complaints of esophageal reflux may occur even without self-induced vomiting, and is generally secondary to diminished competence of the gastroesophageal sphincter.

Gastritis and pyloric erosions are not frequent, but dilatation of the proximal duodenum and jejunum are frequently reported. Gastric perforation is a rare complication of the restrictive type of anorexia.

Constipation, mostly due to the drastically reduced caloric intake, constantly follows weight loss in anorexia, and is generally worsened by the abuse of laxatives. Abdominal pain is generally diffuse but without tenderness. Decreased colonic transit and pelvic floor dysfunction occur in undernourished people with anorexia, and normalize after refeeding. Colonic lesions are mostly secondary to chronic constipation and laxative abuse. Inflammation, atony and dilatation and the so-called cathartic colon characterized by thinness, atrophy and superficial ulcers of the mucosa, retention cysts and mononuclear infiltration of the submucosa are very frequent observations. Occasionally, ischemic necrosis of the segmental ileum and cecum has been reported, possibly resulting from poor blood supply linked to severe malnutrition and dehydration. Rectal prolapse occurs, possibly due to constipation or increased intra-abdominal pressure from forced vomiting [12].

Esophagitis, disordered esophageal motility including lower than normal esophageal sphincter pressure, relaxed sphincter pressure, reduced mean esophageal body contraction and amplitude, altered waveform morphology, and reduced progression occur infrequently in bulimia nervosa, while gastroesophageal reflux, dysphagia and odynophagia are often observed [13].

Gastric capacity is generally increased in relation to the frequency and severity of the binging and the amount of daily food intake [14]. The sensation of maximal fullness occurs sooner than the maximally tolerated gastric pain, which is mostly reduced. Intragastric pressure reached at maximum tolerance is normal. Gastric emptying is slower in bulimia nervosa than in normal subjects, probably due to reduced intragastric pressure for a given volume and a lower gradient between the stomach and duodenum. Rectal prolapse has been reported to occur secondary to constipation, laxative abuse, overzealous exercise and increased intra-abdominal pressure from forced vomiting.

In both types of anorexia nervosa, deficiencies of many specific food components may lead to hepatic abnormalities, including hepatomegaly, increases in serum concentrations of lactate dehydrogenase, aspartate and alanine transaminase, and reduction of cholinesterase and plasma proteins. Diffuse liver steatosis may be observed in the most severe forms of the disorder, occasionally evolving in cirrhosis and disappearing with refeeding. Lower than normal plasma concentrations of glutathione are observed, with higher than normal levels of homocysteine, glycine and glutamine, which points to a decreased utilization of these amino acids for glutathione synthesis and an impairment of transsulfuration [15].

Morphological and functional pancreatic abnormalities are frequent in both types of anorexia, sometimes persisting long after recovery [16]. Morphological changes include atrophy with reduced acinar cells and zymogen granules, increases of fibrous interstitial tissue, cystic dilatation of pancreatic ducts and diffuse calcification. The most specific functional abnormality is a reduction of pancreatic enzyme secretion. Amylase and elastase-1 serum concentrations, specific indices of pancreatic dysfunction, are increased. Pancreatitis may be present, but occurs more frequently during refeeding. Amylase levels are generally elevated, correlating with vomiting frequency. The occurrence of pancreatitis may be facilitated by the duodenal stasis followed by duodenal-pancreatic reflux.

Similar alterations may be present in bulimia nervosa [16].

Cardiovascular abnormalities occur in up to 87% of people with anorexia [17]. They include sinus bradycardia and much less frequently tachycardia, ventricular arrhythmia resulting from electrolyte disturbances, lower than normal heart rate variation between supine and standing posture, lower than normal ratios of low- and mid-frequency to high-frequency power (which may represent a balance between the activities of the cardiac sympathetic symptoms), cardiac failure, reduced atrial and left ventricular volume, reduced mean cardiac output, and reduced mean ascending aortic velocity. Bradycardia of less than 60 beats/min during the day and around 30 beats/min at night, related to an energy-conserving slowing of the metabolic rate, is possibly linked to vagal hypertonus. Heart rate variability correlates inversely with BMI [18].

As reported in simple starvation, electrocardiographic alterations occur frequently in people with both types of anorexia [19]. They are represented by low voltage, prolonged Q time, increased QT dispersion, longer QRS intervals, a shift to the right of the QRS axis, diminished amplitude of the QRS complex and T wave, depression of the ST tract, inversion of the T wave, occasional U waves linked to hypokalemia and hypomagnesemia, and premature atrial and ventricular heart beats. Ventricular tachyarrhythmias, however, are less frequent. The inversion of the T wave and the prolonged Q time, which increases the risk of tachyarrhythmias, prevail in people with the bingeing subtype of anorexia, with more severe hypokalemia and hypomagnesemia. Sometimes, however, electrocardiographic impairments occur also in people without evident electrolytic alterations, possibly linked to hypertonus of the central autonomic system. Most of the electrocardiographic changes are reversible, often improving rapidly with correction of electrolytic disturbances and a return to normal nutrition and hydration. During the refeeding period, a too rapid weight gain may lead to congestive heart failure and arrhythmias, possibly related to hypophosphatemia occurring during the first weeks of nutritional rehabilitation.

Hypotension, both systolic and diastolic, of less than 90/60 mm Hg occurs in up to 85% of people with anorexia [20], usually as a result of chronic volume depletion and orthostatic changes resulting in frequent bouts of dizziness and occasionally frank syncope. Decreased thickness of ventricular walls, with consequent decreased myocardial contractility and subsequent hypovolemia and reduction of cardiac cavities concur to decrease blood pressure.

People with bulimia may show some of the cardiovascular changes seen in anorexia nervosa, but these are much less frequent and less severe [21]. A slightly longer mean QT has been reported. Hypotension is very uncommon in this disorder. Arrhythmias due to electrolytic disturbances may occur in people with severe purging behaviors.

Pulmonary alterations do not occur frequently in anorexia nervosa [22], but can occur as a consequence of vomiting or refeeding phenomena. Pneumomediastinum has been observed in the bulimic subtype of anorexia with and without vomiting. The pathology is due to alveolar rupture and subsequent tracking of air along perivascular planes to the mediastinum and subcutaneous area. Subcutaneous emphysema is diagnosed by palpation of the skin overlying the thorax, which reveals a ‘crunchy' sensation, and is also heard over the pericardium being synchronous to systole. During rapid refeeding, pulmonary edema may result from congestive heart failure with dyspnea, orthopnea and paroxysmal nocturnal dyspnea. On examination, dullness to percussion of the lung fields and crackles or wheeze on auscultation may be found.

Pulmonary alterations are infrequent in bulimia nervosa [22], and are linked mainly to vomiting and ingestion of the material in the lungs or to a rapid increase in intra-alveolar pressure with alveolar rupture and pneumomediastinum. Pulmonary edema due to congestive heart failure is generally observed only in long-lasting and extremely severe cases.

Impaired renal function occurs in 70% of starving people with anorexia, with alterations of glomerular filtration rate and concentration capacity, acute or chronic renal failure, increased blood urea, pitting edema, hypokalemic nephropathy, pyuria, hematuria, and proteinuria. An increased risk of urolithiasis has been noted, possibly linked to a combination of high dietary oxalate intake (from tea, spinach, rhubarb, almonds and cashew nuts), chronic dehydration, low urinary excretion and purging. Hypokalemic nephropathy due to the chronic abuse of diuretics or laxatives may occur. This pathology can lead to chronic renal failure with polyuria, polydipsia and increased serum creatinine concentration. High serum levels of uric acid have been seen and along with increased creatinine are considered a poor prognostic feature of the disease [22].

Renal impairment is not frequent in bulimia nervosa [22], unless the pathology is extremely severe; in such cases, abnormalities similar to anorexia are seen.

The most common alterations of the muscular system observed in people with anorexia are muscular weakness, hypotonia and atrophy, which become evident when starvation is markedly severe [23]. A primary myopathy with prominent atrophy of type II fibers is the major abnormality and differs from that observed in simple starvation, which is represented by a mix of type I and II fiber atrophy. Electromyographic studies have revealed increased polyphasic potentials parallel to increases in plasma creatinine-phosphokinase concentrations. Possible causes of this myopathy are the reduced total body potassium levels and caloric and protein deficiency, together with increased physical activity. No muscular alterations have been reported in people with bulimia.

When anorexia has its onset in childhood, patients have reduced skeletal growth, resulting in short stature. Bone accretion and maturation, characteristic of adolescence, are generally retarded, and bone maturation may even totally cease during active phases of the disease [24]. Treatment and weight restoration induce a growth catch-up, which, however, does not reach the expected growth rate. Around a quarter to a third of people with anorexia suffer from osteoporosis, represented by reduced peak bone mass, decreased mineral density, decreased total body mineral content, pathological fractures and vertebral collapse. These alterations correlate with illness duration and BMI. It is not clear whether strenuous weight-bearing exercise can improve bone density in people with anorexia. Osteoporosis and osteopenia also occur in men with anorexia, but with greater severity than in women. Bilateral osteonecrosis of the talus has been reported in anorexia [25].

Increased bone fractures are also observed in bulimia, although less frequently than in anorexia. It is unknown whether the phenomenon is related to osteoporosis (which generally has not been demonstrated in bulimia) or to increased behavioral impulsivity [26].

In two thirds of patients with anorexia, neutropenia and reduced monocytes occur, with white blood cell numbers lower than 5,000/mm³. Relative lymphocytosis and multilobular polymorphonuclear leukocytes are very frequently seen. This alteration could result from bone marrow hypoplasia and its gelatinous transformation with markedly reduced cell production. Gelatinous transformation and cellular necrosis derive from insufficient medullar nutrition, the former occurring when the caloric deficiency develops gradually and the latter when the starvation is acute and extremely rapid, or when other threatening events (e.g. a severe infection) occur concomitantly. People with anorexia may have bone marrow suppression secondary to excessive consumption of phenolphthalein-containing laxatives. The alteration disappears with normal nutrition and weight recovery [23,27].

Anemia, usually of the normochromic and normocytic type with preserved hemoglobin, is observed in at least one third of people with anorexia [27]. Occasionally, macrocytic anemia may be observed, with elevated mean cell volume due to vitamin B₁₂ deficiency. Acanthocytosis, a disorder of the red blood cell membrane, is also observed and is likely linked to abnormalities of cholesterol metabolism. Iron deficiency anemia occurring in anorexia may be normochromic when hemoglobin is above 11 g/dl, or microcytic, hypochromic and with anisocytosis when hemoglobin is below 11 g/dl. Thrombocytopenia has been described in nearly one third of people with anorexia. Purpura and petechiae are infrequent in anorexia.

People with bulimia do not seem to have significant hematological abnormalities.

In anorexia, glucose metabolism is impaired and, even though glucose concentration may be low-normal, the glucose response to a glucose tolerance test is diabetic-like or flat. Insulin and glucagon concentrations are normal or reduced, and inversely correlated with the degree of weight loss. Glucose ingestion results in prolonged insulin peaks [28].

Lipid alterations occur in 50% of people with anorexia, with hypercholesterolemia linked to an increase in LDL cholesterol and elevated fasting free fatty acid concentration [29]. The cholesterol alteration does not correlate with thyroid dysfunction, severity of weight loss, type of food consumption, vomiting or laxative abuse. It may be related to diminished activity of the 5-α-reductase enzyme system. Decreased concentrations of n-6 polyunsaturated fatty acids have been found. Plasma levels of HDL cholesterol, VLDL cholesterol and triglycerides are normal or increased.

Hypercholesterolemia has been observed in bulimia [1].

People with anorexia generally have a reduced concentration of total blood proteins [15]. In particular, globulin levels, more than albumin, are lower than normal. Muscular mass destruction, typical of the disease, is responsible for protein catabolism. Dehydration, hypovolemia, diminished plasma renal flow and diminished glomerular filtration induce an increase of serum urea. Reduced urinary excretion of methylhistidine, a specific index of muscular catabolism, has been observed. Very low albumin levels seem to be highly predictive of death. Reduced blood levels of the essential amino acids, threonine, valine, isoleucine, leucine, and normal or reduced tryptophan levels (including normal or reduced tryptophan to neutral amino acid ratio) have been reported. The tryptophan/neutral amino acid ratio seems to be higher in people with anorexia who are actively exercising. Uric acid is often elevated as an expression of strenuous physical activity combined with starvation resulting in muscle destruction.

No significant protein alterations have been observed in bulimia nervosa.

In anorexia, electrolytic alterations occur frequently as a consequence of starvation and malnutrition, vomiting, and laxative and diuretic abuse, with ensuing fluid depletion and hypovolemia [30,31]. Hypokalemia, hypochloremia and hypochloremic metabolic alkalosis with increased pCO₂ are the most frequently observed alterations. Phosphate and calcium concentrations are generally normal, but vomiting, diarrhea and abuse of diuretics may result in severe hypophosphatemia, which may also be seen during refeeding as a result of transfer of phosphate into cells for phosphorylation of glucose and for protein synthesis. A quarter of people with anorexia [32] develop hypomagnesemia, refractory hypocalcemia caused by increased urinary calcium excretion with renal calculi production, and hypokalemia, which return to normal after magnesium replacement. Iron deficiency and decreased total iron-binding capacity may occur, generally as a consequence of a lack of iron-rich foods. Zinc is low in plasma, urine and tissues linked to the duration and severity of the disease, and zinc deficiency is due to starvation, reduced intestinal absorption of the metal or increased excretion through sweating. Zinc deficiency per se induces anorexia with related weight loss, delayed growth and sexual development, depressed mood, loss of taste, hair loss, and skin alterations resembling those of anorexia. All metal alterations normalize after nutritional rehabilitation.

Hypercarotenemia, normal plasma levels of vitamin A binding protein and retinol-binding protein are observed especially in the restrictive subtype of anorexia following severe starvation and weight loss [33]. Riboflavin and pyridoxine deficiencies have been reported. Vitamin B₁₂ and folate concentrations in blood are generally low. Vitamin B₁₂ and vitamin C-related pellagra and scurvy have been infrequently reported. Blood 25-hydroxyvitamin D, 1,25-dihydroxyvitamin and 24,25-dihydroxyvitamin concentrations are reduced while vitamin D-binding protein values are normal.

Amenorrhea is the most frequent clinical endocrine alteration occurring in underweight women with anorexia, and has long been considered a key criterion for the diagnosis of anorexia [34,35]. Only recently has it been excluded from the definition of the disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, since it has been recognized that menstruation may still occur even in severely malnourished patients or, on the contrary, it may be absent even when body weight is normal. Hypogonadotropic hypogonadism with reduced secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogens and progesterone are at the basis of amenorrhea. In the acute phase of anorexia, circadian gonadotropin secretion is similar to that of the prepubertal stage, with secretory pulses almost completely absent during the day and occasionally present at night. The hypothalamic-pituitary-gonad (HPG) axis response to the administration of the gonadotropin-releasing hormone (GnRH) results in low or absent secretion of LH and FSH (with a preponderance of the FSH response over the LH), as occurs before pubertal maturation. Since estrogens are synthesized from androgens in the fat tissue and exert a positive feedback on hypothalamic GnRH secretion, a critical minimum amount of fat tissue seems to be necessary for normal HPG axis functioning [36]. Therefore, in low-fat tissue patients with anorexia, a lack of aromatization of androgens to estrogens, with a consequent hypoestrogenemia is probably responsible for HPG axis dysfunction. However, since in some women amenorrhea precedes weight loss or persists after the recovery of body weight [37], factors other than weight changes may be involved in the HPG axis dysfunction, including the exaggerated physical activity of some women with anorexia. Indeed, in female athletes, menstrual dysfunction has been found to correlate with the intensity of physical exercise rather than with fat mass.

Men with anorexia nervosa are characterized by low levels of testosterone and LH, but normal response of the HPG axis to the administration of GnRH [38,39]. Moreover, the exocrine testis function seems to be preserved as suggested by the occurrence of normal blood concentrations of inhibin B, which is a marker of gonadal exocrine activity [39]. Therefore, in men with anorexia nervosa, malnutrition seems to have less impact on the gonadal axis.

Oligomenorrhea or amenorrhea occur in almost half of women with bulimia [35], especially when there is a chronic course of bulimic attacks. Normal or decreased levels of plasma gonadotropins, with reduced circadian pulsatility, and diminished concentrations of estrogens and progesterone may be observed. LH secretion is more deranged in its amplitude than in the frequency of secretory pulses, and the LH response to GnRH is normal or even enhanced. These irregularities have been ascribed to food deficiency and especially to protein malnutrition. In addition, since binging episodes increase plasma prolactin levels, it is possible that repeated hyperprolactinemia could impair HPG axis activity due to the inhibitory action of this hormone on GnRH release.

Normal baseline concentrations of prolactin are generally observed in people with anorexia, even though slightly reduced or increased plasma levels may be found [40]. Normal diurnal and increased nocturnal concentrations of prolactin have been observed in acutely ill patients. The prolactin response to thyrotropin-releasing hormone (TRH) is normal. Paradoxical responses to both GnRH and GHRH have been detected in the acute phase of the disease [41].

Normal, decreased or increased baseline prolactin levels can be observed in people with bulimia, with a prolactin response to TRH that is generally normal [41].

In acutely ill patients with anorexia, triiodothyronine (T₃) levels are lower than normal, reversed T₃ (rT₃) levels (which are biologically inactive) are increased, and thyroxine and thyroid-stimulating hormone (TSH) levels are normal [42]. The lower T₃ levels have been attributed to a reduced peripheral deionization of thyroxine with a simultaneous increased formation of rT₃, which delineates a ‘low T₃ syndrome'. This represents a metabolic adaptation to the chronic reduction in caloric intake since it decreases resting energy expenditure [43]. In spite of the reduced secretion of T₃, TSH is not increased in acutely ill patients with anorexia. This could be due to the fact that during low-energy expenditure, a reduction in endogenous metabolic processes occurs in all cells of the organism, including pituitary thyrotropes, which respond as if the low T₃ levels are sufficient for metabolic needs; in such a condition, TSH secretion does not increase. Even if TSH secretion is unaltered in anorexia, its central regulation is deranged. The TSH response to exogenous TRH is delayed and sometimes lower than normal. Finally, atrophy of the thyroid gland may occur in underweight people with anorexia. This alteration has been related to the low insulin-like growth factor-I (IGF-I) levels since thyroid size is clearly influenced by this peptide.

Basal thyroxine and T₃ concentrations are preserved in people with bulimia, even though low circulating T₃ levels have been observed. Baseline concentrations of TSH are mostly normal in bulimia, whereas the TSH response to TRH can be found to be either normal, blunted or delayed [1].

In emaciated people with anorexia, plasma levels of growth hormone (GH) are increased and the plasma concentration of IGF-I and GH-binding protein is reduced [44]. The concentration of the IGF-binding proteins, especially that of the IGF-binding protein-3, is reduced during starvation, although increased levels of circulating IGF-binding proteins resulting in a decrease of free IGF-I have also been reported [45]. In underweight people with anorexia, the decreased IGF-I production increases GH secretion because of diminished negative feedback. Concomitantly, primary or secondary hypothalamic or suprahypothalamic changes may further affect GH production. Increased GH levels correlate negatively with the amount of calories ingested and decrease with improved nutritional intake even before significant weight recovery has taken place. Since GH-binding protein represents the GH receptor extracellular domain, its reduced blood levels mirror a reduced sensitivity to GH. The decrements of IGF-I and GH-binding protein in severely undernourished people with anorexia, an expression of a resistance to GH, are probably the reason why GH hypersecretion in these individuals does not result in acromegalic symptomatology.

The hypothalamic GH-IGF-I axis dysregulation may contribute to the development of osteopenia since IGF-I has a trophic effect on the bone. In prepubertal subjects, the ‘resistance' to GH may be one of the causes for the growth delay or cessation persisting following treatment, resulting in a final height lower than that genetically determined [46]. Recombinant human IGF-I or GH have been used in people with anorexia to prevent bone loss or bone fractures, and to facilitate a more rapid metabolic recovery. Recombinant human IGF-I in severely osteopenic women with anorexia increases bone turnover markers in the short term, leading to amelioration of bone density after 9 months, with the latter effect being potentiated by concomitant oral contraceptive administration. Moreover, it has been shown that the recombinant human GH in people with anorexia achieves medical and cardiovascular stability more rapidly [47].

Normal or increased GH levels with a normal circadian rhythm are reported in people with bulimia, while circulating IGF-I is reduced [1].

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis are frequently present in people with anorexia, including increased plasma levels of cortisol with normal blood concentrations of adrenocorticotropic hormone (ACTH), and increased urinary cortisol levels in the acute phase of the disease [48]. The circadian rhythm of ACTH is well preserved, but plasma cortisol concentrations are higher than normal throughout the day and have an increased number and amplitude of cortisol secretory bursts, especially during the middle afternoon when values of the hormone should be at their lowest point. These data suggest that the HPA axis in the acute phase of anorexia is hyperactive. Dynamic studies of HPA axis function tend to demonstrate that hypothalamic and/or suprahypothalamic alterations may cause the higher than normal activity of the axis [49]. Indeed, most people with anorexia cannot suppress cortisol production during the dexamethasone suppression test; the cortisol responses to ACTH stimulation are enhanced while the ACTH response to corticotropin-releasing factor (CRF) is reduced/normal in underweight individuals with anorexia [50]. Since these alterations revert with the recovery of body weight, they are considered a consequence of malnutrition, although this is controversial [51]. In experimental animals, CRF provokes anorexia, increased physical activity and reduced sexual behavior, which would support a role for this peptide in the development and/or maintenance of some anorexic symptoms. Clinically, it is intriguing that the hypercortisolemia of people with anorexia never leads to the development of Cushingoid features.

The adrenal glands also secrete androgen dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) under the regulation of the CRF-ACTH system. Evidence for a decreased production of both DHEA and DHEAS in underweight people with anorexia has been widely reported, with a dissociation in the adrenal secretion between cortisol and androgen similar to that observed in the pubertal stage of sexual maturation [52]. This suggests that people with postpubertal acute anorexia may regress to a prepubertal secretory aspect of the reproductive axis (see below), also affecting the HPA androgen system. This reduction, together with the increase in cortisol levels, leads to decreased DHEA to cortisol and DHEAS to cortisol ratios similar to that occurring in the pubertal stage of sexual maturation [53].

In people with bulimia, HPA axis activity is only slightly altered, with morning plasma cortisol concentrations either normal or increased, while urinary excretion of free cortisol and 17-hydroxycorticosteroids as well as cortisol responses to CRF or ACTH are normal. The most widely reported alteration of the HPA axis in bulimia is the nonsuppression of cortisol to a dexamethasone challenge in 20-60% of patients, without significant correlations with severity and chronicity of the illness, concomitant depressive symptoms, or previous history of anorexia. This alteration disappears after successful treatment of bulimia, and is not predictive of treatment outcome [54].

In people with eating disorders, physical complications are very common and usually occur as consequences of nutritional derangements secondary to aberrant eating and abnormal compensatory behaviors. In the most severe cases, these complications represent a significant threat to the patient's life. In emaciated people with anorexia, especially in those who vomit and/or abuse diuretics and laxatives, immediate risks come from electrolytic perturbations and starvation-induced cardiovascular and renal complications. These complications may lead to the development of severe arrhythmias and sudden death. Individuals with a chronic course of anorexia are exposed to consequences of the progressive impairment in bone density, which increases the likelihood of pathological fractures. On the other hand, some of the somatic alterations occurring in the acute phase of anorexia seem to have a protective effect. Indeed, in emaciated people with anorexia, the impaired function of the reproductive axis and the reduced activity of thyroid gland aim to preserve residual energy stores for vital functions and reduce basal metabolic needs.

In bulimia, physical complications are less severe and occur less frequently than in anorexia. Therefore, they rarely represent a serious threat to the patient's life. The most harmful complications are represented by esophageal and/or gastric ruptures, secondary to the massive ingestion of food in the course of binge episodes, and cardiac arrhythmias induced by severe electrolytic imbalance following vomiting and diuretic or laxative abuse.

Although, with a few exceptions, physical complications resolve with the recovery of body weight and the discontinuation of aberrant behaviors, they contribute, together with suicide, to the high mortality of patients with eating disorders. Indeed, anorexia has the highest mortality of any psychiatric diagnosis, estimated at 10% within 10 years of diagnosis, and is the leading cause of death in young females 15-24 years of age. Mortality for bulimia is approximately 1% within 10 years of diagnosis. It is important to remember that even if most of the physical complications of eating disorders do not represent life-threatening conditions, they increase the patients' burden of suffering, impair their quality of life and, therefore, need clinical consideration and appropriate treatment. Therefore, psychiatrists who have patients with anorexia nervosa and bulimia nervosa should be alerted to identify those signs and symptoms that express malnutrition-related physical complications (table 2) and collaborate with medical experts who specialize in the treatment of physical alterations. This will ensure the simultaneous correction of psychopathological and physical aberrations in order to obtain a full and fast recovery from the diseases.