Medical complications in anorexia and bulimia nervosa

Abstract

Anorexia nervosa and bulimia nervosa are eating disorders associated with life-threatening multisystemic medical complications. This narrative review aimed to present the medical complications most associated with these disorders. In anorexia nervosa, many of them are linked to malnutrition and underweight, usually reversible with renutrition and weight restoration, although refeeding can also be linked to some medical complications. Purging behaviours observed in the anorexia nervosa binge-purging subtype and BN have been mainly related to hydrolectrolyte and acid-base disturbances, in addition to local complications. Thus, an early identification and therapeutic intervention of these disorders is considered crucial. Integral medical monitoring should be ensured to prevent potential serious complications from the early stages, with the involvement of physicians, psychologists, nutritionists, and other specialists in a multidisciplinary approach according to the patient's needs.

Resumen

La anorexia nerviosa y bulimia nerviosa son trastornos de la conducta alimentaria asociados a complicaciones médicas multisistémicas que pueden poner en riesgo la vida del paciente. Esta revisión narrativa tiene como objetivo presentar las complicaciones médicas más comúnmente asociadas a estos trastornos. En la anorexia nerviosa, muchas de ellas están ligadas a malnutrición y bajo peso, generalmente reversibles con renutrición y recuperación ponderal, si bien la realimentación también puede presentar complicaciones. Las conductas purgativas observadas en la anorexia nerviosa bulímico-purgativa y la bulimia nerviosa se han relacionado principalmente con un desequilibrio hidroelectrolítico y alteración del equilibrio ácido-base, además de complicaciones locales. Así, se considera crucial la identificación e intervención terapéutica precoz de estos trastornos. Se debe asegurar una monitorización médica exhaustiva para prevenir potenciales complicaciones graves desde estadios iniciales, con una implicación de médicos, psicólogos, nutricionistas y otros especialistas en el abordaje multidisciplinar de las necesidades del paciente.

Introduction

A significant part of the morbidity and mortality attributed to eating disorders (EDs) is due to acute and sub-acute medical complications, with multisystemic involvement.¹ Anorexia nervosa (AN) represents the mental disorder with the highest mortality (5%), secondary to weight loss, malnutrition and medical complications.² While most of these complications usually reverse with weight regain, some occur during renutrition, such as refeeding syndrome. In the bulimic-purging subtype (AN-BP) and bulimia nervosa (BN), the most prevalent and severe complications are linked to purging behaviours, especially vomiting. Thus, electrolyte and acid-base imbalance and local complications are distinguished, with discontinuation of purging behaviours being crucial in their medical management.^1,2

The aim of this study is to conduct a narrative review of the literature focusing on the last 20 years regarding the most commonly described medical complications in adults with AN and BN. It is hoped that this updated review may have an impact on the development of future protocols for the assessment and treatment of AN and BN.

Medical complications

Dermatological

Dermatological conditions are some of the most visible signs in EDs, even in the early stages of their development. Reviews such as Strumia's³ include pioneering studies that have allowed the identification of multiple dermatological complications in these disorders, distinguishing some signs considered as a guide for their diagnosis.^4,5 For example, Russell's sign, which has been characteristically associated with vomiting in BN and AN-BP.⁴

Most skin and mucosal complications in AN occur secondary to caloric restriction, malnutrition and significant weight loss.³ Among the most prevalent is xerosis, which is typically associated with the presence of cracks in acral parts. Sebaceous hyposecretion and vitamin and trace element mineral deficiencies are often involved in its occurrence.³ Xerosis may contribute to the development of other complications such as pruritis, nail dystrophy and hyperpigmentation.³ Along these lines, the predominant intake of carotene-rich vegetables underlies the carotenoderma described in these patients. The loss of subcutaneous cellular tissue secondary to lipolysis leads to the development of pressure ulcers, as well as reduced tolerance to cold, which can manifest as skin conditions such as chilblain. Lanugo is frequently observed on the face, back and abdomen of these patients. It is specifically associated with starvation in the context of AN, in an attempt to conserve body temperature. Thus, it should not be confused with a sign of virilisation unlike hypertrichosis, which has been described as a guiding sign in this disorder.⁴ At the scalp level, however, these patients often suffer from telogen effluvium. Prolonged calorie restriction has also been associated with the appearance of mild-moderate acneiform lesions on the face and back, with excoriation being quite common.⁶ Signs such as acrocyanosis have been described as a common but idiopathic phenomenon in AN, although it has been suggested that acrocyanosis may be related to an attempt to conserve cardiac output.⁵

Although less common than in AN, signs such as acne and telogen effluvium have also been reported in individuals with BN.³ Some complications in these patients are more typical of overweight and obese states, such as stretch marks, due to skin distension, or fat folds. In patients with purging behaviours, skin complications due to adverse effects of some laxatives and diuretics, such as thiazide diuretic therapy-induced photosensitivity, should also be monitored.³

Neurological

AN has been associated with structural and functional involvement of the central and peripheral nervous system. Diffuse atrophy of grey and white matter⁷ has been described, leading to neuropsychological deficits.^8,9 As they do not necessarily reverse with weight recovery,⁹ these deficits have been suggested as vulnerability factors or even as an irreversible consequence of the disorder.² Peripheral involvement includes neuropraxia, secondary to loss of subcutaneous cellular tissue and involved in distal limb weakness.¹⁰ In these patients, dysautonomia may be reflected, for example, in visceral paresis.² Dysautonomia has also been frequently described in BN along to the presence of neuropsychological deficits.^2,8

Sense organs

In patients with AN, loss of fatty tissue around the Eustachian tube and periocular tissue underlies the presence of autophony, enophthalmos and lagophthalmos.^11,12 Hypovitaminosis A has also been associated with corneal involvement leading to vision loss.¹³ As an example of abnormalities in other senses, some studies have reported a 6% prevalence of hyperosmia.¹⁴ In AN-BP and BN, straining to vomit can contribute to the occurrence of epistaxis, papilledema and subconjunctival haemorrhage, with vitreous haemorrhage being a less common but more serious finding.^2,15

Ear, nose and throat

Within EDs, lesions in the oral cavity and dentition are mostly associated with vomiting and are often present from early stages.¹ Exposure to gastric acid, changes in salivary composition, poor oral hygiene or the type of food ingested have been described as triggers for tooth discolouration and hypersensitivity, caries and perimolysis, typically in the anterior upper jaw.^1,2 Mucositis, especially in the palate and oropharynx, can lead to ulceration and scarring,¹ with this inflammatory state also affecting gums, periodontal spaces and lips. Another common disorder is sialadenosis, usually bilateral and accompanied by xerostomia.¹⁶ Dysautonomia and malnutrition may be underlying factors, although their aetiology has not been fully clarified.¹ The increase in glandular size in AN is inversely proportional to body mass index. In BN, it has been described in 25–50% of patients, days after cessation of vomiting. The parotid gland is usually affected in 10–25% of cases,^1,2 although it has also been observed in salivary glands, such as the palatal minor glands.¹⁶ Progression to sialoadenomegaly is rare (0.5% of cases), however, in 10–20% of cases it is accompanied by salivary hyperamylasaemia. Being proportional to the frequency of vomiting, hyperamylasaemia has been suggested as a marker of self-induced vomiting.¹⁷ Precisely, recurrent vomiting favours oropharyngolaryngeal muscle weakness, which could translate into the presence of laryngopharyngeal reflux, odynophagia and dysphagia.¹⁸ Vocal cord involvement secondary to laryngopharyngeal reflux typically presents with dysphonia,¹⁸ proposed as a potential diagnostic sign of BN. In AN, muscle wasting associated with factors such as caloric restriction, weight loss and dysautonomia also contribute to the development of dysphagia, described in up to 20% of patients.¹⁹ This complication may be a limiting factor in their weight recovery.¹⁹

Cardiovascular

The high mortality associated with medical complications in AN is mainly defined by cardiogenic complications. Previous review studies such as Spaulding-Barclay et al.²⁰ detail the different cardiovascular alterations in this disorder. Patients with AN frequently present with both relative hypotension, with a systolic blood pressure < 100 mmHg, and orthostatic hypotension. Hypotension is often accompanied by sinus bradycardia, considered the most common rhythm disorder in AN. It occurs in up to 95% of cases,²⁰ due to the prevalence of vagal tone in an attempt to adapt to the reduced metabolic output.²⁰ The intensity of bradycardia is related to underweight and duration of the disorder.²¹ Thus, an intensification of vagal tone can lead to suppression of the physiological pacemaker with the appearance of autonomic rhythm in another site, such as the junctional rhythm. Tachycardia is often related to the presence of infection, anaemia or other acute condition in AN. However, it is the most common rhythm disturbance in BN, secondary to electrolyte imbalance induced by purging behaviours.¹⁷ Hypokalaemia and hypomagnesaemia have also been associated with QT prolongation, especially in patients with BN and AN-BP.²² As it is not considered an inherent finding in EDs, its manifestation always requires screening for secondary causes, such as an adverse reaction to certain drugs (antiemetics, antipsychotics, etc.).²¹ This abnormality favours the occurrence of bradyarrhythmias, supraventricular tachyarrhythmias and torsade de pointes,²² which have been described as potential causes of sudden death in EDs, together with certain structural abnormalities.²⁰

Cardiac atrophy, especially left ventricular atrophy, and myocardial fibrosis have been reported in AN in about 23% of cases.²³ Although their pathophysiology remains unclear,²⁰ these alterations have been associated with the occurrence of mitral valve prolapse, described in between one and two thirds of patients.¹⁰ Starvation and malnutrition together with structural and cardiac rhythm abnormalities affect myocardial contractility, resulting in reduced ejection fraction in up to 15% of individuals, together with reduced exercise tolerance and fatigue.²⁰ However, reduced ejection fraction may be due to non-cardiogenic complications, such as hypertransaminasemia.²⁰ The degree of malnutrition in AN has also been linked to the occurrence of pericardial effusion, described in one third of cases and usually asymptomatic.^2,20,23 Some cardiovascular complications may be due to the adverse effects of certain purging products, such as ipecac cardiomyopathy. This emetic contains emetine, a cardiac toxin with a cumulative effect that can lead to irreversible myocardial damage.²

Respiratory

Muscle weakness secondary to eating psychopathology in AN involves the respiratory musculature, describing a decrease in lung capacity.²⁴ Similarly, impaired pulmonary surfactant production has been linked to some cases of pneumothorax in this disorder.²⁵ The description of several cases of spontaneous pneumomediastinum in patients with anorexia nervosa restricting subtype (AN-R) has been attributed to massive alveolar rupture (Macklin effect),¹⁰ and alveolar air migration may affect other body spaces.²⁶ Boerhaave’s syndrome is not considered a common cause of pneumomediastinum in EDs, although the effort of vomiting and the not uncommon ingestion of foreign bodies for emetic purposes can lead to oesophageal rupture.^2,17 Precisely, vomiting together with gastro-oesophageal reflux have been associated with the occurrence of bronchiectasis which, together with emphysema, constitute the main structural respiratory changes that have been described in EDs.²⁷

Gastrointestinal

AN-related gastrointestinal disturbances are reported in up to 90% of cases.²⁸ Malnutrition and dysautonomia underlie the muscle weakness and peristaltic disturbances observed in the lower third of the oesophagus. Consequently, tonic lower oesophageal sphincter involvement favours gastro-oesophageal reflux, with dysphagia and dyspepsia typically associated with reflux. In AN-BP and BN, emetic behaviour is especially related to reflux, which also leads to oesophagitis.²⁹ The finding of Barrett's oesophagus has been described in some case studies,³⁰ with the prevalence of oesophageal neoplasm being around 10% in patients with recurrent vomiting.³¹

Changes in gastrointestinal permeability, dysbiosis and myenteric dysautonomia have been described as contributing factors to gastric and intestinal involvement in AN.³² However, in these patients, a functional component has also been reported to influence clinical manifestations such as irritable bowel syndrome.²⁹ Gastroparesis usually occurs in 50% of cases and involves a slowing of gastric emptying, with the presence of abdominal distension and postprandial fullness, non-specific abdominal discomfort and nausea.^2,10 It also promotes gastro-oesophageal reflux and dilatation of the gastric cavity,³³ which has also been associated with superior mesenteric artery syndrome in AN.³⁴ This entity is a consequence of visceral fat loss and has been more frequently described in cases of AN-R.¹⁰ Although gastric capacity is increased in BN, there is decreased relaxation resulting in delayed gastric emptying, decreased cholecystokinin release and enteric dysautonomia.³³ Gastric dilatation carries an increased risk of intestinal obstruction, ischaemia³⁵ and gastric rupture,³⁶ as well as bronchoaspiration, which can lead to respiratory failure.²⁶ Pelvic floor and anal sphincter muscle weakness is reported in approximately 40% of patients.¹⁰ Together with gastroparesis, these are factors that lead to constipation in AN, which occurs in more than 60% of cases and carries an increased risk of complications such as rectal prolapse.¹⁰ Laxative abuse in AN-BP and BN, especially prokinetics, and myenteric dysautonomia will favour colonic atony and cathartic colon, which have also been associated with constipation.¹⁷

Hepatopancreatic

Calorie restriction in AN patients has been associated with the presence of hepatitis by an underlying mechanism of cellular apoptosis with signs of autophagy.³⁷ However, hepatic hypoperfusion secondary to hypovolaemia and oxidative stress associated with hepatic iron and lipid deposition have also been linked to liver dysfunction in these patients.³⁸ Liver involvement has been associated with moderate hypertransaminasemia (50% of cases) and hypoglycaemia, which is often asymptomatic and proportional to the degree of malnutrition.³⁷ Hypoglycaemia can also be a consequence of intense physical activity or even a sign of infection in these patients. In any case, it is considered a medical emergency because of its potential complications, including seizures, comatose state and cardiac involvement, increasing the risk of sudden death. Pancreatitis is a rare complication, associated with low weight, malnutrition and hypoperfusion in AN.³⁴ However, some cases of recurrent idiopathic pancreatitis have been reported in both AN and BN, with pancreatic enzyme mobilisation.³⁹

Endocrine-metabolic

Functional abnormalities affecting several endocrine systems and hypothalamic-pituitary axes have been described, particularly in AN patients.⁴⁰ In a situation of nutritional and caloric deficit, these changes mostly respond to a physiological adaptation of the organism in an attempt to maintain energy homeostasis.⁴⁰

Thus, reduced levels of anorexigenic hormones versus increased orexigenic signalling have been observed in AN. Hypoleptinaemia has been associated with a loss of adipose tissue,⁴¹ although findings regarding other adipocytokines such as adiponectin have been inconclusive.⁴² The elevation of neuropeptide Y, however, is considered paradoxical and a contributor to the pathophysiology of the disorder.⁴³ Changes that promote euglycaemia include increased ghrelin, which promotes gluconeogenesis and lipolysis through stimulation of growth hormone (GH) and the hypothalamic-pituitary-adrenal axis. Along the same lines, this would explain the low levels of insulin-like growth factor 1 (IGF-1), which induces GH secretion by a negative feedback mechanism. This, however, may lead to the GH resistance described in AN,⁴⁴ with factors such as hypoinsulinaemia or increased hepatic and adipose production of fibroblast growth factor also being involved. Hypercortisolaemia would also have a compensatory function against hypoglycaemia. It has been reported in up to one third of patients and is considered to be proportional to underweight.⁴⁵ Similar to Cushing's syndrome, increased cortisol is involved in other complications such as bone loss and muscle wasting, insulin resistance, gastric ulceration and mood changes.⁴⁶ It also promotes centripetal fat accumulation, which may be particularly evident during weight recovery.

Regarding the thyroid axis, alterations compatible with the euthyroid patient syndrome, typically described in different non-thyroid systemic diseases, have been reported.⁴⁷ On the other hand, the involvement of the gonadal axis is linked to reproductive complications in these patients. Increased ghrelin, hypercortisolaemia and hypoleptinaemia contribute to inhibition of the gonadal axis. In fact, regression to prepubertal hormonal status has been described in AN, secondary to the reduction of oestrogen, progesterone and androgens.⁴⁸ This leads to hypoprolactinaemia and hypothalamic amenorrhoea, which is present in more than 80% of cases.¹⁰ Nevertheless, the use of contraception is still justified, as unplanned pregnancy has been described in up to 30% of cases, secondary to the presence of ovulation without menstruation.⁴⁹ During gestation, a history of AN has been associated with an increased risk of complications such as hyperemesis gravidarum, miscarriage and low birth weight, caesarean section and increased perinatal mortality.⁵⁰ In these patients, close monitoring of pregnancy and postpartum is advised, especially if it coincides with an active phase of the disorder. Low levels of oxytocin, which plays an anorexigenic role, may interfere with the birth process and lactation, as well as with bone metabolism and mood regulation in AN patients.⁵¹ In males, hypoandrogenism leads to decreased libido and sexual potency. Regarding BN, oligomenorrhoea is usually more common than amenorrhoea, and an increased risk of miscarriage during pregnancy has been reported.¹⁷

Renal

Local complications at various levels associated with purging behaviour, mainly vomiting, have been discussed in previous sections. However, electrolyte and acid-base balance disturbances account for the bulk of the morbidity and mortality associated with this behaviour, especially in BN.¹ Thus, an increased risk of serious multisystem complications such as seizures, heart failure and sudden death has been described. The most common disorders are hypokalaemia and metabolic alkalosis.⁵ Both can be part of the Pseudo-Bartter syndrome, which can occur after abrupt cessation of recurrent purging behavior.⁵² The resulting oedema results in sudden weight gain in these patients, which may precipitate a relapse to purging behaviours with a compensatory purpose. Hypokalaemia has also been associated with local renal damage in the form of nephropathy, which in some cases may require haemodialysis. Hypomagnesaemia is often associated with the use of diuretics, especially loop diuretics, and can cause refractory hypokalaemia. Although hyperkalaemia is less common, diuretic abuse such as spironolactone should be ruled out.⁴⁰ Enemas cause alterations similar to the use of other laxative products, particularly hyperphosphataemia, due to their composition.⁵³

A significant proportion of renal disorders in AN are mainly associated with the AN-BP subtype.⁵⁴ Hypokalaemia has been reported in 20% of cases and the most common sodium abnormality is hyponatraemia (7% cases).⁵⁴ Although antidiuretic hormone-related diseases could be involved in sodium abnormalities, they are not commonly reported in AN.⁵⁴ In the context of renutrition, it is important to note that different electrolyte changes can lead to refeeding syndrome. This is defined as a decrease in one, two or more electrolytes (phosphorus, potassium, magnesium) and/or organ dysfunction secondary to one of them or to vitamin B1 deficiency (Table 1), occurring within five days of caloric reintroduction.⁵⁵

Table 1.

Refeeding syndrome characteristics.

Refeeding syndrome
Laboratory criteria	Clinical features
Hypophosphatemia^a	Rhabdomyolysis
Hypokalaemia^a	Cardiorespiratory failure
Hypomagnesaemia^a	Haemolysis
Vitamin B1 deficiency	Seizures

a

Decrease of 10–20% (mild), 20–30% (moderate), or > 30% (severe).

Musculoskeletal

Specific to AN, sarcopenia and muscle atrophy contribute to muscle weakness.¹⁰ In most of these patients, increased bone resorption mediates the loss of bone mineral mass, which starts in early stages and mainly affects trabecular bone.¹⁰ Longer duration of the disorder, younger age, lower body mass index, hypovitaminosis D, sarcopenia, different metabolic alterations related to GH resistance and excessive physical activity are involved in this bone loss severity.^54,56 Consequently, these patients have an increased risk of osteopenia, osteoporosis and fractures in the long term, as it is not a completely reversible disorder.⁵⁶ Bone loss and osteoporosis have not been reported in normal-weight BN,⁵⁶ although it could occur if there is a restrictive pattern or a history of AN.

Haemato-immunological and infectious diseases

Bone marrow hypoplasia secondary to gelatinous transformation of the bone marrow has been observed in AN.⁵⁴ Although pancytopenia may occur, normocytic anaemia (22–83% of cases) and leukopenia with neutropenia (22–79% of cases) are the most common findings.⁵⁷ Thrombocytopenia has been reported in 10–25% of cases, associated with low thrombopoietin levels due to liver dysfunction.⁵⁷ Thus, these patients have an increased risk of spontaneous haemorrhage, purpura and petechial skin and mucosal lesions.⁶ Some cases of disseminated intravascular coagulation syndrome have also been reported in AN.⁵⁸

The association between leukopenia and increased risk of infection in AN is inconclusive in the literature.² However, attenuated febrile reaction and atypical mobilisation of inflammatory markers may delay the diagnosis of an infectious process and contribute to increased infectious morbidity and mortality in this disorder.⁶ Therefore, it has been suggested that the confluence of several signs such as hypothermia, tachycardia, hypoglycaemia and hypoalbuminaemia should induce screening for infectious pathology in these patients.⁶ Respiratory and gastrointestinal muscle weakness has been associated with the risk of opportunistic or bronchoaspiration lung infection, without necessarily being associated with underlying lung disease.⁵⁹ However, alterations in innate immunity and the existence of bronchiectasis and emphysema have been particularly associated with mycobacterial infections (tuberculous and non-tuberculous) in these patients.⁶⁰ Furthermore, skin lesions such as striae and fat folds, mucosal inflammation or visceral perforation represent other potential foci of infection in patients with an ED.¹

Conclusions

EDs are common illnesses and many of the signs and symptoms associated with them may be a reason for consultation with different health professionals. This review aims to be of use to all professionals, both within and outside the mental health field, in the recognition of potential medical complications associated with EDs. The aim is to promote early detection and treatment of these disorders and their complications, which has an important prognostic impact.

Funding

This study has been partially funded by the Health Research Fund (FIS) of the Carlos III Institute of Health (ISCIII) (FIS PI20/00132), co-financed by ERDF/European Regional Development Fund (ERDF) funds, 'A way to build Europe'. CIBERObn is an ISCIII initiative. This work has also been funded by the Instituto de Salud Carlos III (ISCIII) through grant CM21/00172 (co-funded by the European Social Fund, ESF, “Investing in your future”); AGAUR-Generalitat de Catalunya (2021-SGR-00824); and the European Union Horizon 2020 Research and Innovation Programme (PRIME/H2020, Prevention and Remediation of Insulin Multimorbidity in Europe, grant no. 847879 and eprObes no. 101080219).

Conflict of interest

Fernando Fernández Aranda received consulting fees from Novo Nordisk and editorial fees as Editor-in-Chief from Wiley. The rest of the authors reported no conflicts of interest.

Acknowledgements

We wish to thank the CERCA Programme/Generalitat de Catalunya for their institutional support.