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Abstract

In anorexia nervosa, under-nutrition and weight regulatory behaviours such as vomiting and laxative abuse can lead to a range of biochemical problems. Hypokalaemia is the most common electrolyte abnormality. Metabolic alkalosis occurs in patients who vomit or abuse diuretics and acidosis in those misusing laxatives. Hyponatraemia is often due to excessive water ingestion, but may also occur in chronic energy deprivation or diuretic misuse. Urea and creatinine are generally low and normal concentrations may mask dehydration or renal dysfunction. Abnormalities of liver enzymes are predominantly characterized by elevation of aminotransferases, which may occur before or during refeeding. The serum albumin is usually normal, even in severely malnourished patients. Amenorrhoea is due to hypogonadotrophic hypogonadism. Reduced concentrations of free T4 and free T3 are frequently reported and T4 is preferentially converted to reverse T3. Cortisol is elevated but the response to adrenocorticotrophic hormone is normal. Hypoglycaemia is common. Hypercholesterolaemia is a common finding but its significance for cardiovascular risk is uncertain. A number of micronutrient deficiencies can occur. Other abnormalities include hyperamylasaemia, hypercarotenaemia and elevated creatine kinase. There is an increased prevalence of eating disorders in type 1 diabetes and the intentional omission of insulin is associated with impaired metabolic control. Refeeding may produce electrolyte abnormalities, hyper- and hypoglycaemia, acute thiamin depletion and fluid balance disturbance; careful biochemical monitoring and thiamin replacement are therefore essential during refeeding. Future research should address the management of electrolyte problems, the role of leptin and micronutrients, and the possible use of biochemical markers in risk stratification.

Introduction

Anorexia nervosa is a psychiatric disorder with profound physical consequences, which may affect any physiological system. Sufferers limit their food intake in order to lose weight and may also employ other weight-regulatory behaviours such as self-induced vomiting, misuse of laxatives or excessive exercise. Less common means of weight control include misuse of diuretics, weight loss drugs or thyroxine and use of amphetamines to suppress appetite; misuse of ipecacuanha appears to be relatively common in the USA but is rare in the UK. A significant number of patients consume excessive quantities of caffeine-containing drinks. Patients with type 1 diabetes may give themselves inadequate amounts of insulin in order to control their weight. Some patients achieve weight loss by dietary restriction alone (restricting type) while others also show bulimic behaviours such as bingeing, vomiting and laxative misuse (binge-eating/purging type).

The disorder has a prevalence of around 0.2–0.8% among young women and a peak age of onset in early to mid-adolescence; approximately 10% of those affected are men. The disorder can occur in prepubertal children but is more common in those over the age of 12. Amenorrhoea is currently one of the diagnostic criteria but is a non-specific feature of weight loss and its usefulness in diagnosis is therefore questionable. Anorexia nervosa can result in major, and potentially life-threatening, physical complications. These include the following:

Bradycardia and hypotension;

Electrocardiogram abnormalities and cardiac arrhythmias;

Hypothermia;

Electrolyte disturbances;

Micronutrient deficiencies;

Bone marrow suppression;

Neuropathy;

Myopathy;

Gastrointestinal disturbance;

Oesophagitis;

Osteoporosis.

The combination of under-nutrition with weight regulatory behaviours such as vomiting and laxative abuse can lead to a range of acute and chronic biochemical problems. This review will describe the common biochemical problems that occur in patients with anorexia nervosa. It will not deal in detail with treatment, except where an understanding of the underlying biochemistry should guide management, or areas of research which are not directly relevant to clinical practice.

Electrolyte disturbances

Hypokalaemia is the most common electrolyte abnormality found in anorexia nervosa. As in other clinical situations, however, there are complex inter-relationships between electrolytes and an abnormality in one should prompt measurement of others.¹

Hypokalaemia

Hypokalaemia may be due to vomiting, laxative misuse or, occasionally, misuse of diuretics. As potassium is primarily an intracellular ion, plasma concentrations are a poor reflection of total body stores, particularly in the presence of acid–base disturbance. It has been shown that a normal plasma potassium may be associated with significant depletion of total body stores.²

A number of mechanisms are thought to underlie hypokalaemia. In laxative misuse, potassium is lost directly from the gut. In patients who vomit, however, the mechanism is more complex and direct loss of potassium in the vomit is a relatively minor factor.³ In these cases, hypokalaemia is primarily due to metabolic alkalosis, which is secondary to loss of hydrogen ions in the vomit. This leads to increased delivery of bicarbonate to the kidney and increased renal excretion of potassium.⁴ It has been suggested that, in chronic cases, a raised bicarbonate may be a more sensitive marker of potassium depletion than the plasma potassium.¹ An additional mechanism may be the pH-dependent shift of potassium from the extracellular space into the cells.³ In patients who have become volume depleted, secondary hyperaldosteronism may also contribute to both potassium loss and metabolic alkalosis by promoting renal conservation of sodium and bicarbonate and excretion of potassium.^5,6 In these cases, restoration of plasma volume and sodium replacement is required, in addition to potassium replacement, in order to suppress excessive secretion of renin and aldosterone.

Measurement of urinary potassium may help to distinguish vomiting (in which the urinary potassium is increased) from laxative misuse (in which it is reduced).^5,7 In clinical practice, however, it is not uncommon for patients to combine the two behaviours. The biochemical picture in patients who vomit or misuse diuretics may be very similar to that of Bartter's syndrome, with hypokalaemic alkalosis and increased urinary potassium, and this has been named pseudo-Bartter's syndrome. Urinary chloride excretion is low in metabolic alkalosis of extra-renal origin but normal or raised when it is due to renal tubular disease. Measurement of the urinary chloride:creatinine ratio may therefore help to distinguish pseudo-Bartter's syndrome from renal causes of hypokalaemic metabolic alkalosis; however, results may be misleading in chronic metabolic alkalosis with severe hypokalaemia and in diuretic-induced metabolic alkalosis.⁸

Definitive treatment of hypokalaemia requires treatment of the behaviours which cause it. However, this may take time and it is important to manage the biochemical disturbance in the interim. As the plasma potassium is only an approximate guide to intracellular concentrations, the author's practice is to maintain the plasma potassium within the normal range. The first line of treatment is oral potassium supplementation (e.g. Sando-K, HK Pharma Ltd, Hitchin, UK; 2–8 tablets per day, taken at a time when the patient is not vomiting). In severe cases, intravenous replacement is required, but this produces only a temporary improvement if the underlying behaviour continues and ongoing oral treatment is therefore essential. For those patients who vomit and in whom normokalaemia cannot be maintained with oral supplementation, the use of a proton pump inhibitor (PPI) may be a useful second-line treatment.^9,10 By reducing the secretion of gastric acid, these drugs minimize the loss of hydrogen ions in the vomit and the consequent alkalosis, and thereby reduce the compensatory renal excretion of potassium. It has been argued that PPIs will be ineffective unless sodium depletion is also corrected,⁶ but it is uncertain whether sodium depletion is a significant factor in all patients and whether volume replacement is always required;⁹ these questions need to be addressed in a randomized controlled trial.

Magnesium

Intake of magnesium is deficient in a significant proportion of patients with anorexia nervosa¹¹ and hypomagnesaemia can occur before or during refeeding.^12,13 Intravenous rehydration, particularly with saline, can precipitate hypomagnesaemia by increasing magnesium excretion in the urine.¹⁴ Magnesium is lost in both faeces and urine and hypomagnesaemia is therefore a potential consequence of both laxative and diuretic misuse.¹⁴ Patients who also misuse alcohol seem to be at particular risk of hypomagnesaemia. Hypomagnesemia may be associated with hypokalaemia, in which case magnesium replacement will be required before hypokalaemia can be corrected; treatment-resistant hypokalaemia should therefore prompt measurement of the plasma magnesium.

Calcium

Hypocalcaemia can occur either in the starved state or during the course of refeeding.^13,14 It is sometimes misdiagnosed on the basis of a low corrected calcium when the serum albumin is artificially elevated by dehydration. The serum calcium concentration may drop during refeeding when phosphate supplementation is given to correct hypophosphataemia. Treatment-resistant hypocalcaemia may be due to hypomagnesaemia, which requires treatment before hypocalcaemia can be corrected; even mild hypomagnesaemia may be responsible for refractory hypocalcaemia.¹⁵

Phosphate

Hypophosphataemia is most commonly encountered as part of the refeeding syndrome (described below), where it results from an increased carbohydrate load in the presence of phosphate depletion. However, a similar mechanism can result in hypophosphataemia during binge eating¹⁶ or attempts at self-treatment.¹⁷ Abuse of laxatives or diuretics may result in hypophosphataemia, but it has also been reported in the absence of these behaviours and prior to refeeding; those who also abuse alcohol are probably at increased risk.^13,18–22 Hypercortisolaemia, which is well recognized in anorexia nervosa, may contribute to phosphate depletion by increasing urinary phosphate excretion.²³ Chronic acidosis reduces renal tubular reabsorption of phosphate and may therefore contribute to hypophosphataemia in those who misuse laxatives.²⁴ As with other electrolytes that are predominantly intracellular, serum concentrations are not necessarily an accurate reflection of tissue stores and a normal serum phosphate concentration does not exclude total body depletion.²⁵ For a comprehensive review of hypophosphataemia in anorexia nervosa, please see Haglin.²⁶

Acid–base disturbances

Hypochloraemic metabolic alkalosis occurs in patients who vomit or abuse diuretics; in both cases, the alkalosis is likely to be associated with hypokalaemia.^27–29 In those who vomit, loss of hydrogen ions in the vomit is likely to be a significant factor; however, as noted above, sodium depletion and secondary hyperaldosteronism may also contribute to the alkalosis.⁶ Another contributory factor in those who vomit is hypochloraemia, which leads to reduced chloride delivery to the kidney and consequent bicarbonate retention.⁷ In those who also misuse laxatives or alcohol, the additional presence of hypomagnesaemia may produce a picture similar to that seen in Gitelman's syndrome, in which metabolic alkalosis is associated with hypokalaemia, hypomagnesaemia and hypocalciuria. In patients who misuse laxatives, there is significant loss of potassium and bicarbonate in the faeces and the picture is therefore typically of hypokalaemic hyperchloraemic metabolic acidosis.²⁷ However, in one series of patients with hypokalaemia secondary to laxative misuse, the authors report substantial elevation of the serum pCO₂, consistent with metabolic alkalosis; they speculate that this is due to secondary hyperaldosteronism.³

Salt and water balance

Hyponatraemia is a common problem in anorexia nervosa but it is relatively under-recognized. The most common cause is excessive water ingestion, leading to dilutional hyponatraemia. In some cases this is deliberate and is done in order to increase weight prior to weighing (‘water loading’). Water loading should be suspected when there is an inconsistent pattern of weight gain or when the weight gain is disproportionate to the calorie intake. It can sometimes be detected by measuring the plasma sodium shortly after weighing the patient. Some patients drink excessive amounts of water for other reasons and may be unaware of the amount of water that they are drinking; they may do so in order to suppress feelings of hunger or because they have difficulty distinguishing between thirst and hunger.

A rarer cause of hyponatraemia is misuse of diuretics. Depletion of plasma volume, sometimes associated with hypovolaemic hyponatramia, has been reported in severely malnourished patients who abuse diuretics or use long-term sodium restriction as a means of controlling their weight. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may occur in patients with space occupying intracranial lesions, which can present with symptoms similar to those of anorexia nervosa. Intracranial pathology should always be considered in patients with eating disorders when the clinical features are atypical and a computed tomography or magnetic resonance imaging scan of the head may be required.

In some cases, it is not possible to identify excessive fluid intake or other causative behaviour. These patients are often in a state of chronic and severe energy deprivation. The biochemical picture is typically of low sodium with a relatively high potassium and it is sometimes necessary to exclude Addisons's disease. Research in other forms of malnutrition suggests two possible mechanisms which may explain this phenomenon: oxidative damage to the cell membrane (leading to increased permeability to sodium and potassium ions) and energy-dependent failure of the sodium/potassium pump to maintain the appropriate gradient across the cell membrane. In kwashiorkor (oedematous malnutrition), there is a cell membrane leak: the intracellular potassium is reduced and the sodium is increased.^28,30,31 It has been shown experimentally that reduction in concentrations of glutathione to those seen in kwashiorkor leads to an increase in the permeability of the red cell membrane to sodium and potassium, which will lead to influx of sodium into the cells and efflux of potassium from them.^32,33 It has also been shown in malnourished children that leukocytes have slow sodium pumps: the rate constant for sodium efflux is low and the glycoside-sensitive sodium flux rate is diminished.^30,34

Data on the hormonal regulation of salt and water balance in anorexia nervosa are inconsistent. There is some evidence that patients show increased aldosterone secretion in response to angiotensin II infusion and walking despite normal baseline concentrations of aldosterone; this may be due to chronic sodium deficiency.^35,36 There is also evidence for the dysregulation and hypersecretion of vasopressin in anorexia nervosa.^37–43 Evrard et al. ⁴² reported that patients with anorexia nervosa had higher concentrations of vasopressin than controls and an impaired vasopressin response to water deprivation. Frank et al. ⁴⁰ found that vasopressin concentrations in the cerebrospinal fluid were elevated in women who had recovered from the binge eating/purging type of anorexia nervosa. Similarly, Demitrack et al. ⁴³ and Gold et al. ³⁹ reported over-secretion of vasopressin into the cerebrospinal fluid. However, Connan et al. ⁴⁴ found no evidence of up-regulated vasopressin activity and Aperia et al. ⁴⁵ found reduced urinary concentrating ability both before and after administration of vasopressin, suggesting an intrinsic renal problem.

The management of hyponatramia depends on identification of the cause. This is sometimes easily established by taking a history of fluid intake but patients often underestimate their intake. Measurement of urinary sodium may help to distinguish excessive water ingestion from SIADH. In excessive fluid ingestion, urinary sodium will be low, whereas in SIADH, the urinary sodium should be above 30 mmol/L (unless the patient is sodium depleted). Salt and water depletion due to vomiting may occasionally cause hyponatraemia, although this is rare in the author's experience.

Where excessive water intake is identified, fluid restriction is necessary and this may require admission to hospital in severe cases. However, hyponatramia is often chronic and well tolerated and fluid intake should be reduced cautiously. In cases where hyponatramia is secondary to severe energy depletion, it will improve as the energy deficit is corrected. Abuse of diuretics should be tackled at the behavioural level.

Renal function

Urea and creatinine are normally low in anorexia nervosa, due to decreased protein intake and loss of muscle mass.⁴⁶ Urea or creatinine concentrations towards the top of the normal range can therefore indicate significant dehydration and/or renal compromise.⁴⁷ Estimates of glomerular filtration rate (GFR) which are based on serum creatinine concentration and standardized equations are therefore likely to overestimate GFR in anorexic patients.^48,49 The effects of malnutrition mean that other markers of haemoconcentration, such as the haematocrit and haemoglobin, may also be normal.⁵⁰ Unrecognized renal impairment may, in turn, artificially elevate plasma concentrations of potassium, magnesium and phosphate and mask low total body concentrations of these electrolytes.⁵¹

It has been reported in one study that anorexic patients who abuse laxatives have reduced 24-h creatinine clearance, compared with those with the restrictive form of the disease; however, these findings were confounded by the fact that those in the laxative abusing group also had a longer duration of illness.⁵² In the related disorder of bulimia nervosa, chronic severe hypokalaemia has been reported as leading to a progressive decline in renal function and histological changes suggestive of chronic glomerular injury.⁵³ Chronic tubulo-interstitial nephropathy has been reported and has been generally attributed to chronic hypokalaemia.^47,54,55 Alexandridis et al.²³ report a case of reversible tubular dysfunction associated with severe hypophosphataemia and hypouricaemia. There is an increased prevalence of urolithiasis in anorexia nervosa, probably due to chronic dehydration and a high dietary intake of oxalate.^54,55 Rhabdomyolyis due to hypophosphataemia may lead to acute renal failure or chronic tubulo-interstitial disease and glomerulosclerosis.⁴⁷

Liver function

Abnormalities of liver enzymes are well recognized in anorexia nervosa. The picture is typically a hepatitic one, with predominant elevation of aminotransferases.^46,56–59 These abnormalities are usually asymptomatic and self-limiting, but in rare cases severe liver damage or failure can occur.^60–65 Abnormalities may occur before refeeding^56,64,66,67 and improve as nutrition improves^60,67 or arise during the course of refeeding.⁶⁸

These abnormalities are commonly referred to as ‘nutritional hepatitis’ but the cause is not established. Possible mechanisms include liver hypoperfusion and ischaemia,^63,66 hepatocyte autophagy⁶⁹ and depletion of glutathione.⁷⁰ In patients who are being refed, it has been suggested that increased insulin secretion secondary to carbohydrate ingestion results in lipogenesis and fatty change in the liver.^71–73

Serum proteins

The serum albumin is usually normal, even in severely malnourished patients.^74–80 The reason for this is not known; it may reflect relative preservation of protein intake, adaptive reduction in protein catabolism or a shift of albumin from the extravascular to the intravascular pool.⁸¹ Hypoalbuminaemia may indicate occult infection⁸² and should not be attributed simply to malnutrition. When it does occur, hypoalbuminaemia is associated with a poor prognosis.^83,84

Nova et al. ⁷⁵ reported low transferrin concentrations, which improved with weight restoration, but other studies have found normal concentrations of prealbumin, retinol-binding protein, caeruloplasmin and transferrin.^78,80,85 In anorexia nervosa, serum concentrations of sex hormone binding globulin (SHBG) are higher than in controls and decrease with refeeding; unlike albumin, SHBG concentration does not seem to be influenced by inflammation and may therefore be a better marker of nutritional status than the albumin.^85,86 Insulin-like growth factor 1 (IGF-1) may also prove useful as a nutritional marker.⁷⁶

Bone chemistry

Calcium and bone metabolism are important because of the high prevalence of osteoporosis, which occurs in 13–38% of those with anorexia nervosa.⁸⁷ Osteomalacia can also occur but is rare.^88,89 The causes of reduced bone mineral density are not clearly established but are likely to include hypogonadism, growth hormone resistance, low concentrations of IGF-1, hypercortisolism and possibly disturbed secretion of leptin.^87,90,91

It is uncertain whether reduced calcium intake is a significant factor in the pathogenesis of osteoporosis in anorexia nervosa. Misra et al. ⁹² found no difference in calcium intake between patients with anorexia nervosa and healthy controls, whereas Hadigan et al. ¹¹ found that more than half of their patients failed to meet the recommended dietary allowance for vitamin D and calcium. A review of published studies⁹³ concluded that low calcium intake was likely to contribute to decreased bone mineral density. Vitamin D concentrations have generally been found to be normal.^94,95 Fonseca et al. ⁹⁶ found that 25-hydroxyvitamin D concentrations were low in 88% of those studied, whereas 1,25-dihydroxyvitamin D was low in only 12%. By contrast, Aarskog et al. ⁹⁷ and Caillot-Augusseau et al. ⁹⁸ found normal concentrations of 25-hydroxyvitamin D and Aarskog et al. ⁹⁷ found low concentrations of 1,25-dihydroxyvitamin D in at least some subjects. Concentrations of parathyroid hormone were normal in two studies.^94,98 Results of these studies are summarized in Table 1. Despite the uncertainty about the role of calcium and vitamin D deficiency, treatment with supplemental calcium and vitamin D is common.⁹⁹

Table 1

Studies of Vitamin D and parathyroid hormone concentrations

Study	25-Hydroxyvitamin D units	1,25-Hydroxyvitamin D	Parathyroid hormone	Notes
Kiriike et al. ⁹⁴ (1992)	Mean concentration normal	Mean concentration normal but reduced in 1/29	Mean concentration normal but reduced in 3/29	Results compared with normal range
				PTH was 276 ± 115 pg/mL.
				1,25 (OH)₂D was 31.4 ± 14.7 pg/mL.
				25OHD was 23.4 ng/mL ± 7.7
Van Binsbergen et al. ⁹⁵ (1988)	Mean concentration normal			20 patients compared with 10 controls.
Van Binsbergen et al. ⁹⁵ (1988)	Mean concentration normal			25OHD was 40.8 nmol/L in patients versus 56.8 nmol/L in controls but this was not statistically significant
Fonseca et al. ⁹⁶ (1988)	Reduced in 15/17	Reduced in 2/17	Raised in 2/17	17 patients compared with healthy controls.
				Median 25OHD was 8 nmol/L versus 38 nmol/L in controls. Median 1,25(OH)₂D did not differ between patients and controls.
				Median PTH was 63 pmol/L versus 58 pmol/L in controls
Aarskog et al. ⁹⁷ (1986)	Mean concentration normal	Mean concentration reduced		12 patients compared with 81 controls.
				1,25-(OH)₂D was 71 pmol/L versus 124 pmol/L.
				25OHD concentrations were 85.7 nmol/L versus 86.7 nmol/L
Caillot-Augusseau et al. ⁹⁸ (2000)	Normal concentrations in all subjects		Normal concentrations in all subjects	9 patients compared with 6 healthy controls.
				PTH was 24.9 ± 12.6 ng/L versus 27.2 ± 8.0 ng/L in controls.
				25-OH-D₃ was 31.0 ± 15.8 ng/mL; no control data given

PTH, parathyroid hormone

In adults with anorexia nervosa, markers of bone metabolism generally suggest uncoupling of bone turnover, with increased bone resorption and decreased bone formation; adolescents have decreased bone turnover overall.⁹⁰ However, Lennkh et al. ¹⁰⁰ found increased levels of markers of bone resorption with normal markers of bone formation and Carmichael and Carmichael¹⁰¹ found no changes in bone formation or resorption parameters. Body mass index is correlated positively with markers of bone formation and negatively with markers of bone resorption.¹⁰² Refeeding increases bone formation markers and decreases bone resorption markers.^98,103

Hypothalamic–pituitary–gonadal axis

The typical finding in anorexia nervosa is hypogonadotrophic hypogonadism, with low concentrations of follicle stimulating hormone, luteinizing hormone and oestradiol. There is a diminished response to gonadotrophin releasing hormone (GnRH) and a prepubertal pattern of luteinizing hormone release.^104–107 The prepubertal sex hormone picture is thought to be due to low concentrations of leptin,^108,109 which plays a role in the secretion of GnRH.¹¹⁰ In men, an equivalent sequence leads to low concentrations of testosterone.^{109,111–115} In rare cases, hypogonadotrophic hypogonadism may be part of more widespread hypothalamic–pituitary dysfunction, which also involves thyroid function.¹¹¹

Hypothalamic–pituitary–thyroid axis

Reduced concentrations of free T4 (FT4) and free T3 (FT3) are frequently reported.^116–121 In order to conserve energy, T4 is preferentially converted to reverse T3; low concentrations of T3 are therefore accompanied by high concentrations of reverse T3.¹²² Data on thyroid-stimulating hormone (TSH) concentration are conflicting, with some studies reporting that the TSH is low^116,123 and others finding normal concentrations.^119,120,124 There is one report of four cases where the TSH was elevated, in association with a low T3 and low free T4.¹²¹

The TSH response to TSH-releasing hormone (TRH) is abnormal in some, but not all, patients.^{117,121,123,125} Even when the TSH response to TRH is delayed, the T3 response may be normal.¹²¹ As with gonadal function, it has been suggested that dysfunction of the hypothalmic–pitutatry–thyroid axis in anorexia nervosa is due to reduced secretion of leptin.^111,116,126 Weight gain leads to an increase in FT3, FT4 and TSH;^116,120,121 the ratio of T3/T4 is elevated and the ratio of rT3/T4 is reduced, suggesting increased conversion of T4 to T3.¹¹⁸ The increase in T3 which occurs with weight gain is reflected in an increase in resting energy expenditure.¹²⁴

Hypothalamic–pituitary–adrenal axis

Hypercortisolaemia is a consistently reported feature of anorexia nervosa.¹²⁷ Compared with controls, there are significant elevations in serum cortisol concentrations, cortisol area under the curve values and urinary free cortisol corrected for creatinine and surface area.^128–130 Salivary cortisol is also elevated and some patients lose the normal circadian rhythm of cortisol secretion.¹³¹ The cortisol response to adrenocorticotrophic hormone has generally been found to be normal,^132–135 although both increased^136,137 and blunted responses¹³⁸ have been reported.

Glucose metabolism

Hypoglycaemia is a common finding in anorexia nervosa and mild degrees are often well tolerated.¹ However, severe hypoglycaemia is a grave prognostic sign and an indication for immediate hospitalization. Insulin concentrations have generally been found to be low or normal.^139–142

Lipid abnormalities

A number of studies have found high concentrations of total cholesterol in patients with anorexia nervosa.^143–150 Several, though not all, studies, have found elevated concentrations of both LDL- and HDL-cholesterol.^143,145,146 The results of these studies are shown in Table 2. The aetiology of these changes is not fully understood. It has been suggested that low concentrations of T3 and reduced catabolism may allow lipoprotein concentrations to be maintained.^143,147 In support of this, Rigaud et al. ¹⁴³ found that plasma lipoprotein was positively correlated with FT3 and Weinbrenner et al. ¹⁴⁸ found that FT3 and FT4 predicted LDL-cholesterol concentrations. On the other hand, Matzkin et al. ¹⁴⁴ found that elevated cholesterol was inversely related to T3 and T4 and Ohwada et al. ¹⁴⁵ found no relationship between cholesterol and thyroid hormones. Increased synthesis of cholesterol does not seem to be a factor.^151,152 Increased synthesis and decreased catabolism of triglyceride-rich lipoproteins may be a factor and high concentrations of campesterol and beta-sitosterol suggest that increased resorption of endogenous cholesterol may be implicated.^147,152

Table 2

Lipid abnormalities in anorexia nervosa*

Study	Mean total cholesterol (mmol/L)	Mean HDL cholesterol (mmol/L)	Mean LDL (mmol/L)	Mean triglycerides (mmol/L)	Study details
Rigaud et al. ¹⁴³ (2009)	10.55 (190 mg/100 mL)	2.72 (50 mg/100 mL)	7.11 (128 mg/100 mL)	5.77 (104 mg/100 mL)	120 patients and 119 controls
Matzkin et al. ¹⁴⁴ (2007)	10.62 (191.3 mg/dL)	3.11 (56.1 mg/dL)	6.45 (116.2 mg/dL)	5.08 (91.6 mg/dL)	30 patients and 30 controls
Misra et al. ²²³ (2006)	8.03 (144.7 mg/dL)	2.64 (47.6 mg/dL)	4.63 (83.5 mg/dL)	3.8 (68.4 mg/dL)	23 patients and 20 controls
Matzkin et al. ¹⁴⁶ (2006)	10.63 (191.4 mg/dL)	3.29 (59.3 mg/dL)	6.64 (119.6 mg/dL)	4.52 (81.4 mg/dL)	300 patients and 216 controls
Zak et al. ¹⁴⁷ (2005)	5.52	1.58	3.49	1.21	16 patients and 25 controls
Ohwada et al. ¹⁴⁵ (2006)	8.62 (155.2 mg/dL)	3.51 (63.2 mg/dL)	4.5 (81 mg/dL)	4.08 (73.6 mg/dL)	24 patients and 5 controls
Boland et al. ¹⁴⁹ (2001)	11.05 (199 mg/dL)	3.38 (61 mg/dL)	6.55 (118 mg/dL)	5.11 (92 mg/dL)	101 patients and 95 controls
Case et al. ¹⁵⁰ (1999)	5.7	1.49	3.40	1.5	9 patients and 10 controls

*Where necessary, units have been converted to mmol/L for ease of comparison. Original figures are given in brackets

The significance of these findings for cardiovascular risk is uncertain. The bulk of the available evidence suggests that lipid abnormalities improve or resolve on recovery from anorexia nervosa.^143,145,146 Where there is diagnostic uncertainty, elevated serum cholesterol may be useful in distinguishing anorexia nervosa from inflammatory bowel disease or malabsorptive states, in which the cholesterol is usually at the lower limit of normal or subnormal.¹⁵³

Micronutrients

Intake of many micronutrients is reduced in patients with anorexia nervosa^11,154,155 and a number of micronutrient deficiencies have been identified. These include zinc, copper, vitamin C, riboflavin and vitamin B₆.^{154,156–164} However, the clinical significance of many of these deficiencies is unclear and the relationship between blood concentrations and whole-body status is complex for many micronutrients. Moreover, assays for some of these vitamins and trace elements may not always be readily available. It is therefore prudent to assume that patients with anorexia nervosa are at risk of multiple micronutrient deficiencies and treat all patients with a complete micronutrient supplement such as Forceval (Alliance Pharmaceuticals Ltd, Chippenham, UK).⁹⁹ Additional supplementation with B vitamins is also recommended during the early stages of refeeding.¹⁶⁵

Thiamin deficiency occurs in 38% of patients¹⁶⁶ and is of particular importance because of thiamin's role in carbohydrate metabolism. Deficiency may also contribute to the cognitive impairment which is commonly seen in severe anorexia nervosa. There has been particular interest in zinc deficiency, which may cause alterations in taste as well as a variety of neuropsychiatric symptoms. One study found that the use of zinc supplements increased the rate of weight gain,¹⁶⁷ but this finding has yet to be replicated. Vitamin A deficiency is rare but can lead to keratomalacia and consequent blindness.¹⁶⁸

Miscellaneous abnormalities

Hyperamylasaemia occurs in patients who vomit and is usually due to the release of salivary amylase.^{153,169–171} However, pancreatitis may occur in patients with anorexia nervosa, particularly during the course of refeeding^172–174 and measurement of serum lipase may be required to distinguish pancreatitis from hyperamylasaemia of salivary origin.¹⁷¹ A raised salivary amylase may prove a clue to concealed vomiting¹⁶⁹ but a normal amylase does not exclude it.

Hypercarotenaemia may cause orange discolouration of the skin (carotenoderma), which is sometimes mistaken for jaundice. Mean concentrations of serum beta-carotene are higher in anorexia nervosa than in the normal population¹⁴⁹ and a number of studies have reported hypercarotenaemia in a significant number of subjects.^{155,175–178} However, plasma concentrations of retinol and retinol-binding protein appear to be normal.^156,157,179 The cause of hypercarotenaemia in anorexia nervosa is not clear. In some cases, it is due to excessive ingestion of fruit and vegetables which are high in carotene but this may not always be the case.¹⁸⁰ Elevated concentrations of creatine kinase are commonly seen in patients who exercise to excess.

Anorexia nervosa and type 1 diabetes

There is an increased prevalence of eating disorders and disordered eating among patients with type 1 diabetes.^181–188 The combination of the two disorders leads to an increased risk of both acute and chronic complications^189–192 and an increased mortality rate.¹⁹³

A significant proportion of adolescent and young women with type 1 diabetes admit to the intentional omission of insulin.^{183,185,191,194,195} Insulin omission is associated with poor metabolic control, an increased incidence of complications such as neuropathy, retinopathy and nephropathy and an increased frequency of hospital admissions for ketoacidosis.^{182,189,196–198} Disturbed eating further impairs glycaemic control.^189,194 Undiagnosed eating disorders are probably a significant and under-recognized cause of poor metabolic control in young people with diabetes.

Biochemical changes during refeeding

The shift from a catabolic to an anabolic state produces profound biochemical changes, which are often referred to as the ‘refeeding syndrome’. In fact, refeeding induces changes in three distinct areas: electrolytes, fluid balance and micronutrient status.¹⁹⁹ The refeeding syndrome can occur in patients receiving parenteral, enteral or oral refeeding.

The earliest biochemical change is usually hypophosphataemia, which typically occurs in the first 24–72 h of refeeding.^{17,19,22,71,200–206} In starvation, tissue catabolism leads to loss of phosphorus but compensatory changes in renal excretion usually maintain normal serum concentrations;¹⁹⁹ a normal serum phosphate concentration therefore does not rule out total body depletion.²⁶ Once refeeding begins, increased carbohydrate metabolism leads to increased production of adenosine triphosphate and 2,3 diphosphoglycerate and consequently an increased demand for phosphate.⁷¹ There is also an increased demand for phosphate for protein synthesis.²⁶ In addition, carbohydrate intake stimulates the secretion of insulin, which leads to a shift of phosphate into the cells. Clinical consequences of hypophosphataemia include cardiac failure and arrhythmias, respiratory failure, delirium, neuromuscular dysfunction, rhabdomyolysis and abnormalities of red blood cell morphology. Some experts advocate prophylactic phosphate supplementation,^26,201 but this is not universal practice and may induce hypocalcaemia.

Hypomagnesaemia and hypokalaemia also occur during refeeding, again due to pre-existing depletion and increased uptake into cells secondary to increased secretion of insulin.⁷¹ Hypomagnesaemia can occur as late as the third week of refeeding.¹² Hypomagnesaemia may in turn lead to hypokalaemia (due to impaired activity of Na/K-ATPase) and hypocalcaemia (due to impaired parathyroid function). Although not typically considered part of the refeeding syndrome, hypocalcaemia may also be part of the clinical picture.²⁰⁶ Hyperglycaemia may develop, particularly when enteral feeding is employed.^199,207 Hypoglycaemia may be due to an excessive insulin response to feeding (‘dumping’).¹ Carbohydrate ingestion also increases carbon dioxide production, which can lead to hypercapnia and potentially even respiratory failure.²⁰⁸

Acute depletion of thiamin is an important and avoidable complication of refeeding. In the starved state, the requirement for thiamin is low but it increases dramatically when carbohydrate intake is increased. Acute thiamin depletion may cause Wernicke syndrome, cardiac failure or lactic acidosis.⁷¹ It is therefore essential to give thiamin before initiating refeeding and continue it during the early stages. The effect of refeeding on other micronutrients has been less well studied but it is possible that acute selenium deficiency also contributes to cardiac dysfunction during refeeding.^208,209

Refeeding leads to oedema in a significant proportion of patients. In most cases, this is isolated peripheral oedema, without evidence of cardiac failure (‘refeeding oedema’). The cause is not firmly established but it is more common in those who vomit or misuse laxatives and may well be due to persistently high concentrations of aldosterone as a result of chronic hypovolaemia.²⁷ It has been shown experimentally that fasting causes natriuresis and refeeding with carbohydrate promotes sodium retention;²¹⁰ increased secretion of insulin, which increases sodium retention by the kidney, may therefore be a factor.^71,211,212

The risk of refeeding syndrome can be reduced by restricting calorie intake during the early stages, monitoring electrolyte status closely and correcting abnormalities promptly, and giving a micronutrient supplement. Most experts recommend correcting electrolyte disturbances before refeeding, although the NICE Guideline for Nutrition Support in Adults ¹⁶⁵ suggests that this is unnecessary and recommends routine electrolyte supplementation instead. For reviews of the refeeding syndrome, please see Crook et al.,²⁰⁸ Solomon and Kirby,¹⁹⁹ and Stanga et al.²¹³ Comprehensive advice on its prevention and management are available in the Royal College of Psychiatrists’ Guidelines for the Nutritional Management of Anorexia Nervosa ⁹⁹ and the guidelines for the management of medically compromised patients (MARSIPAN) published by the Royal College of Psychiatrists and the Royal College of Physicians.²¹⁴

Future directions

There have been considerable advances in the clinical biochemistry of anorexia nervosa in recent years, and the field has benefited from an increased understanding of the general principles of refeeding severely malnourished patients. However, there are still significant areas of uncertainty: for example, the timing of electrolyte replacement remains controversial and the pathophysiology of fluid balance changes is not established.

Changes in leptin secretion in anorexia nervosa have received much attention (please see Hebebrand et al. for a review),²¹⁵ but their relevance to clinical management is not yet clear. As a sensitive indicator of fat stores, which also has a key role in initiating menstruation, leptin may prove to be a useful marker of adequate weight restoration. Bone metabolism in anorexia nervosa is still incompletely understood, although there has been promising research into the role of IGF-1.^216–220 The possibility that hypoleptinaemia contributes to reduced bone mineral density requires further study.^221,222 A greater understanding of the mechanisms underlying bone formation and resorption in anorexia nervosa should lead to more effective treatment of osteoporosis in the future. Micronutrients, with the possible exception of zinc and thiamin, have been little studied, despite the variety of problems which deficiencies can cause. Deficiencies of several micronutrients are known to cause neuropsychiatric symptoms and further research is needed into the possible role of nutritional factors in causing or maintaining the psychopathology of anorexia nervosa.

Finally, one of the most important unanswered clinical questions in the field is how to stratify risk and identify those patients who need urgent and intensive treatment in hospital. Biochemical markers have the potential to contribute to the identification of high-risk patients. Profound hypoglycaemia and electrolyte abnormalities such as hypokalaemia are clearly important but may be absent even in patients who go on to have a fatal outcome. Other useful indicators might include inflammatory markers, measures of oxidative stress and sensitive markers of myocardial damage. Potential biomarkers will need to be evaluated in a large-scale prospective study.

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not applicable.

Guarantor: APW.

Contributorship: APW is the sole author.

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The clinical biochemistry of anorexia nervosa

Abstract

Introduction

Electrolyte disturbances

Hypokalaemia

Magnesium

Calcium

Phosphate

Acid–base disturbances

Salt and water balance

Renal function

Liver function

Serum proteins

Bone chemistry

Hypothalamic–pituitary–gonadal axis

Hypothalamic–pituitary–thyroid axis

Hypothalamic–pituitary–adrenal axis

Glucose metabolism

Lipid abnormalities

Micronutrients

Miscellaneous abnormalities

Anorexia nervosa and type 1 diabetes

Biochemical changes during refeeding

Future directions

DECLARATIONS

References