Linear Growth in Anorexia Nervosa

Anorexia nervosa is a serious psychiatric disease characterised by refusal of food, marked weight loss, and disturbance in body image (1). It is a relatively common condition with a lifetime prevalence of 2.2% in women and may occur in 1% of adolescent girls and up to 4% of college-age young women (2). Up to 10% of cases are seen in boys and men, and the incidence in this group appears to be increasing. The age of presentation of anorexia nervosa is decreasing and, in fact, it is likely that the majority of cases have their initial onset between the ages of 10 and 20 years (2). Significant medical complications range from micronutrient deficiencies to severe cardiac abnormalities (1). Life-threatening complications, however, are less likely in early-onset anorexia nervosa. General signs of severe starvation include peripheral cyanosis, hypothermia, bradycardia, and dizziness. Many young patients present with electrocardiograph abnormalities, the most common of which include sinus bradycardia, prolonged corrected QT interval, and increased vagal tone. Gastrointestinal signs may include constipation, oesophageal varices, hepatic steatosis, abnormal gastric motility, and pancreatitis. Within a few days of reintroduction to feeds, some patients can develop a refeeding syndrome which includes fluid and electrolyte disorders, especially hypophosphatemia, along with neurological, pulmonary, cardiac, neuromuscular, and haematological complications. Commonly encountered endocrine problems include growth retardation, osteoporosis, and hypogonadism. EVIDENCE OF GROWTH RETARDATION Impaired linear growth and the possibility of short stature are significant medical complications in adolescents with anorexia nervosa. One of the first studies linking height and anorexia nervosa examined 71 patients of a mean age of 13.1 years at diagnosis (3). Mean weight loss was 25% of their premorbid weight. With a few exceptions, patients with anorexia nervosa continued to grow at their expected rate and ultimately reached their expected height despite weight losses of 1% up to 45% of their premorbid body weight. The 4 patients with the greatest height-decline percentile, however, were boys. In adolescent children, short stature is more likely to be associated with an early age of onset of symptoms as well as a low body mass index (4). The investigators also report that those who present for the first time at an older age may also have short stature (4). Childhood risk factors for anorexia nervosa until the age of 30 years may include infant feeding problems and a history of undereating (5), and it is unclear whether these problems contribute to the likelihood of short stature in this group of patients who present late. MECHANISMS OF GROWTH RETARDATION The neuroendocrine control of growth hormone (GH) secretion from the anterior pituitary is regulated by hypothalamic GH-releasing hormone and somatostatin, which is closely linked to nutritional status through the interaction of a number of circulating hormones and additional modulatory peptides at the level of both the pituitary and the hypothalamus. In anorexia nervosa, growth retardation can be attributed to a number of alterations in this hormonal milieu (6). These include low levels of thyroxine and triiodothyronine, elevated levels of cortisol, low levels of sex hormones, and changes in the growth hormone-insulin-like growth factor 1 (IGF-1) axis. Studies of adolescents with anorexia nervosa have consistently reported low serum levels of IGF-1 and increased levels of GH secretion, suggesting a degree of GH resistance. It is also possible that these patients may have a degree of GH neurosecretory dysfunction and this may be related to the associated hypercortisolism. ENDOCRINE THERAPY FOR IMPROVING GROWTH Arrested growth and development is recognised to be a relatively severe manifestation of anorexia nervosa and may be an indication for hospitalisation (7). Although the management of the underlying eating disorder and its associated state of poor nutrition remains the priority, improving growth by manipulating the endocrine axis may be a clinical consideration in some cases (1). It is also possible that a bone age delay and the presence of delayed puberty may be associated with better growth potential. In a placebo-controlled trial of 20 patients in whom 13 were administered recombinant human GH (rhGH) in 6 months, a higher IGF-1, triiodothyronine, circulating platelet level, cardiac output, and oral intake were recorded by 3 months (8). The treatment group was also recorded as having a higher fasting plasma glucose and a lower high-density lipoprotein cholesterol. In another placebo-controlled trial of recombinant human IGF-1 (rhIGF-1), patients were randomised into 4 groups: rhIGF-1 and oestrogen, rhIGF-1 alone, oestrogen alone, and no active treatment (9). After 3 months, administration of rhIGF-1 alone was associated with an increased IGF-1 and IGF-binding protein (IGFBP)-2 level but a decreased level of IGFBP-3 and increased bone turnover in favour of resorption. Addition of oestrogen was not associated with a reduction in IGFBP-3 or an increase in bone resorption. At 9 months, a beneficial effect on bone health was noticed in those groups who received oestrogen, and this tended to be more marked in the group who received a combination of rhIGF-1 and oestrogen who seemed to have the greatest increase in lean mass and the greatest reduction in net bone resorption (10). SUMMARY Anorexia nervosa affects children and adolescents during their period of adolescent growth, and its incidence is increasing. Whilst addressing the nutritional deficits and the underlying disease remains the cornerstone of overall management of the growth retardation, these patients will benefit from a thorough endocrine review. There are no published studies that report any beneficial effects of endocrine manipulation of growth in these patients, but studies in young adults support further exploration of this area.