Since the early part of the twentieth century a recurring theme has been the possibility that anorexia nervosa is primarily caused by an endocrine or cerebral disturbance. From 1916 there was much preoccupation with the concept of Simmonds' cachexia/55 the assumed result of latent disease of the pituitary gland. There was diagnostic confusion between anorexia nervosa and hypopituitarism which was only clarified much later when it became known that in true hypopituitarism weight loss and emaciation are uncommon. Hormonal deficits indicative of impaired pituitary function are indeed common in anorexia nervosa, but are merely a secondary manifestation of prolonged malnutrition.
Interest in the neuroendocrinology of anorexia nervosa led to the formulation of the hypothalamic model. (7,56) From the beginning the model was aimed at explaining pathogenesis rather than aetiology; it was not considered an alternative to the psychological origin for anorexia nervosa, but a means of explaining a constellation of disturbed neural mechanisms, as follows:
1. a disordered regulation of food intake;
2. a neuroendocrine disorder affecting mainly the hypothalamic- anterior pituitary-gonadal axis;
3. a disturbance in the regulation of body temperature.
It was known that these functions all reside within the complex of hypothalamic physiology. A 'feeding centre' had been described in the lateral hypothalamus because bilateral lesions there induced self-starvation and death in rats. ^/j A 'satiety centre' in the ventromedial hypothalamus whose destruction caused obesity had previously been described. Over the years it has become clearer that many of the disturbances could be attributed to the patients' malnutrition, as demonstrated by experimental studies in healthy young women who were asked to follow a weight reducing diet. It was found that ovarian function is extremely sensitive to even small restrictions of caloric intake which often lead to impaired menstrual function.(59)
Interest in the hypothalamic model was fuelled early on by clinical reports of patients diagnosed as suffering from anorexia nervosa who were later found to have cerebral lesions, especially tumours of the hypothalamus. (6.9 More recently, occult intracranial tumours have been detected, masquerading as anorexia nervosa in young children/61
Neuroimaging studies in anorexia nervosa have led to findings suggestive of an atrophy of the brain. CT has disclosed a widening of the cerebral sulci and less frequently an enlargement of the ventricles. (62) The outer cerebrospinal fluid spaces were enlarged markedly in 36 per cent of the patients. When the CT examination was repeated after weight gain 3 months later, the widening of the sulci had disappeared in 42 per cent of the patients who had previously shown this finding. In other patients, however, the widening remained unaltered for 1 year after body weight had returned to normal.
Functional neuroimaging techniques have also been applied to research in anorexia nervosa. Fifteen children with anorexia nervosa were investigated by means of single-photon emission CT which provides a measure of regional cerebral blood flow. In the majority of the children there was an above-critical difference in the regional cerebral blood flow between the temporal lobes. Hypoperfusion was found on the left side in eight children and on the right side in five. Follow-up scans were undertaken in three children after they had returned to normal weight; the reduced regional cerebral blood flow in the temporal lobe persisted on the same side as the initial scan. The authors concluded that there was an underlying primary neurological abnormality—an imbalance of the limbic system which in turn led to a hypothalamic-pituitary abnormality. Caution is advisable when interpreting functional neuroimaging studies as it is extremely difficult to have a control group with children.
The strongest argument in favour of a biomedical causation of anorexia nervosa is the evidence that genetic factors have a role to play. The evidence is mainly derived through the classical method of comparing the concordance rates for the illness in monozygotic and dizygotic twins. The first sizeable series of twins studied came from the Maudsley Hospital and St George's Hospital in London, and revealed a higher concordance rate for monozygotic than for dizygotic twins. (64) Among the 30 twin pairs the concordance rates were 56 per cent among monozygotic twins compared with 7 per cent among dizygotic twins. The authors concluded that there is a genetic predisposition to anorexia nervosa.
Tentative calculations of the 'heritability' of anorexia nervosa suggested that it accounts for as much as 80 per cent of the variance. It remains uncertain how the genetic vulnerability to anorexia nervosa expresses itself in terms of the pathogenesis of this disorder. An interesting proposal is that this vulnerability confers a weakness of the homeostatic mechanisms which normally ensure weight restoration after a period of weight loss. This hypothesis would explain why in Western society, where dieting behaviour is common, those who are genetically vulnerable would be likely to develop anorexia nervosa. te5)
There is also evidence for a familial aggregation of anorexia nervosa. This does not necessarily mean that the origin of the disorder is genetic because environmental factors in common must also be considered. In a series of 387 first-degree relatives of 97 probands with anorexia nervosa it was found that the illness occurred in 4.1 per cent of the first-degree relatives of the anorexic probands, whereas no case was found among relatives of the controls who were probands with a primary major affective disorder or with various non-affective conditions. (69 The authors concluded that anorexia nervosa was familial with intergenerational transmission. It was roughly eight times more common in female first-degree relatives of anorexic probands than in the general population, and absent in the relatives of probands with major affective disorder, thus indicating a specificity in the risk of transmission of anorexia nervosa and an absence of shared familial liability with affective disorders.
Since the early 1970s, the hypothalamic model of anorexia nervosa has been transformed from a consideration of anatomical 'centres' to 'systems' involving neurotransmitters. Much evidence has been presented to show that a wide range of neurotransmitters modulate feeding behaviour, and it was only a small conceptual step to suggest that some were involved in the pathophysiology of eating disorders. At first the neurotransmitters considered were mainly the monoamine systems—noradrenaline (norepinephrine), dopamine, and serotonin. In addition, opioids, the peptide cholecystokinin, and the hormones corticotrophin-releasing factor and vasopressin have also been thought to play a part in the pathogenesis of eating disorders. During recent years the main interest has been focused on the role of serotonin (5-hydroxytryptamine, 5-HT) in the control of natural appetite, especially those aspects concerning the phenomenon of satiety, mediated through a range of processes called the 'satiety cascade'. (67> There is now strong evidence that pharmacological activation of serotonin leads to an inhibition of food consumption. It was also postulated that a defect in serotonin metabolism confers a vulnerability to the development of an eating disorder. (6.Z.)
A boost to the concept of altered serotonin activity in anorexia nervosa has come from research showing that these patients while still underweight had significant reductions in cerebrospinal fluid 5-hydroxyindoleacetic acid ( 5-HIAA). The levels became normal when the patients were retested 2 months after they reached their target weight/68 In order to test whether these findings were secondary to malnutrition, the researchers resorted to the ingenious step of studying patients after 'recovery' when they had reached normal weight. They found elevated levels of cerebrospinal fluid 5-HIAA, possibly indicating increased serotonin activity contributing to the abnormal eating behaviour which often persists in patients who have otherwise recovered. (69) The arguments against this simple model of enhanced serotonin activity as a vulnerability trait in anorexia nervosa should be briefly represented. In two recent studies serotonin function was again assessed in long-term weight-restored anorectics. The investigators used a dynamic neuroendocrine challenge with D-fenfluramine as a specific probe of serotonin function which mediates the release of prolactin. If there were any persistent abnormality in serotonin function, the response to this challenge test should differ from that in normal controls. In fact, the rise in prolactin levels was very similar in former patients and normal controls. Accordingly, these studies failed to support the notion of increased central serotonin function as a vulnerability trait in anorexia nervosa. (7,71)
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