Life 3cieaces Vol . 18, pp . 1341-1348, 1976 . Printed is the II.S .A .
Pergamoa Press
MINIREVIEiP BIOIAGICAL ASPECTS OF AMORESIA NBRVOSA Mark Lupton, Laura Simoa, Virginia Harry, and Harold L . 1Clawana Divisions of Neurology and Endocrinology, Department of Medicine, and the Psychosomatic and Psychiatric Institute, Michael Reese Hospital and Medical Center, Chicago, Illinois 60616 Anorexia nervosa has been recognized as a distinct disorder for yell over a hundred years . Originally described in 1868 by Gull (1) in England and in 1873 by Laségue (2) in France, this disease continues to puzzle with its peculiar combination of paychological and physiological manifestations . Since refusal to eat may occur in various physiologic or psychiatric diseases other than anorexia nervosa, the differential diagnosis is sometimes complicated . Current published criteria (3) res++ir e (A)
Aqe of onset prior to 25
(H)
Anorexia with accompanying weight loss of at least 25 percent of original body weight
(C)
A distorted implacable attitude towards eating, food, or weight that overrides hunger, admonitions, reassurance and threats, e .g ., (1) denial of illness with a failure to recognise nutritional needs, (2) apparent enjoyment in losing weight with overt manifestations that food refusal ie a pleasurable indulgence, (3) a desired body image of eztrenn thinness with overt evidence that it is rewarding to the patient to achieve and maintain this state, and (4) unusual hoarding or handling of food
(D)
No known medical illness that could account for the anorexia and weight loss
(E)
At least two of the following manifeatationes (1) amenorrhea, (2) laaugo, (3) bradycardia (persistent resting pulse of 60 or leas), (4) periods of overactivity, (5) episodes of bulimia, or (6) vomiting (this may be self induced) .
It should ba noted that men as well as women may develop anorexia nervosa . This was noted by Gull (4) in his more extensive 1874 description, but aubssquaat focusing on the symptom of amenorrhea as a key diagnostic feature distracted attention from hale patients with a similar syndrome, but, of course, without amenorrhea . There is now good agreement with Gull that males may alw have anorexia nervosa (5, 6, 7) . Tha average annual incidence of anorexia nervosa is estimated at being 0 .24 to 0 .61 cases par 100,000 population (8) . üomea are affected about 10 to 20 times more frequently than nen (7) . The average age of onset is prior to age 25, with rare cases being reported before age 10 (9) or after age 40 (10) . The prognosis for recovery is generally related to aqa of onset, with poat~ubertal adolescents tending to be most asverely affected . The incidence of mortality rangea from five percent (11) to 20 percent (10, 1341
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12) . Seidensticker and Tzaqournia presented a series of 60 patients hospitalized with anorexia nervosa and followed for up to ten years (10) . Sixty eight percent were either "satisfactory" (i .e ., essentially normal) or "partially satisfactory," 14 percent were "unsatisfactory," and 17 percent had died of malnutrition, intercurrent infection, suicide, or other miscellaneous causes . Curiously, various treatment schedules, including combinations of psychotherapy, drug therapy, tube feedings, and prolonged hospitalizations had equal success. Gull noted in his original description that spontaneous remission often occurs if supportive nutritional therapy can be continued. over months or years (4) . The central clinical problem in anorexia nervosa is weight lose . Patients with anorexia nervosa can lose more than 50 percent of their original body weight (10) . Many of the physical manifestations of anorexia nervosa, including pallor, relative hypotension, bradycardia, leukopenia, dry skin, lanugo hair, abnormalities of glucose tolerance tests, and constipation may be manifeatationa of generalized malnutrition (13, 14), and need not be related to the pathophysiology of anorexia nervosa per se . There are, however, a variety of metabolic changes which would suggest a wide-spread hypothalamic dysfunction in anorexia nervosa . This association of anorexia nervosa with hypothalamic dysfunction is supported by the observation of occasional cases of hypothalamic tumors presenting with anorexia nervosa-like symptoms (15, 16) . It is the purpose of this report to review whether there is evidence that the metabolic disturbances in anorexia nervosa may be related to a hypothalamic dysfunction which is not simply a result of malnutrition . The coexistence of both a psychiatric disturbance and of a separate hypothalamic dysfunction suggests an underlying neurotransmitter abnormality that would be common to both types of dysfunction (17) . The metabolic disturbances of anorexia nervosa are primarily hypothalamic . The traditional hypothalamicrpituitary-end organ relationships will first be reviewed and then other nonrpituitary hypothalamic functions . Thyro id Function Patients who are severely malnourished, whether fry anorexia nervosa or Thus 20 from starvation, often have a characteristic hypoa~etabolic state. percent of Warren and Vende Wiele's patients with anorexia nervosa had a low calculated basal metabolic rate (18) . Keys et al . also noted low basal metabolic rates to be present in patients with malnutrition but without anorexia nervosa (13) . This hypometabolic state resembles myxedema (a disease also described by Gull) and led to many investigations of thyroid metabolism in patients with anorexia nervosa, although their hyperactivity would suggest that they are anything but hypothyroid. Thyroid function studies have in fact been uniformly normal (18, 19, 20, 21) . These include PBI, TBG, T4 , T3~ resin uptake, RAI uptake . A low serum thyroxine by column has been noted, but this has also been noted in chronically ill patients (22) . Adrenal Function Anorexia nervosa has also been compared with hypoadrenalism . Patients with anorexia nervosa have often been reported to have low urinary 17-ketosteroids, and, less often, to have low 17-hydroxycorticoids . Thus five of eight patients studied by Garfinkel et aZ . (21) had below normal urine 17ketosteroids, although all had normal 17-hydroxycorticoida . Danowski et al . (23) found low urinary 17-ketosteroida in six of 16 (31 percent) patients, and Warren and Vende Wiele found low 17-ketosteroids in 18 of 42 patients (42 percent with anorexia nervosa (18)). Despite this finding of low 17-ketosteroids in the urine, which in usual circumstances denotes hypoadrenaliam, these same
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authors have found normal or paradoxially elevated levels of plasma cortisol . Comparisons with other starvation states suggest that these changes are not unique to anorexia nervosa . Cooks et aZ . (24) studied 33 patients with chronic malnutrition in comparison with 96 patients who were "normal" nourished . The starved patients had a low 24 hour urine 17-ketoateroid, an impaired urinary 17-ketosteroid and 17-hydroxycorticoid response to ACTH, sad a delayed rate of disappearance of cortisol from the plasma . In these patients both the resting plasma cortisol level and adrenocortical response to acute hypoglycemic stress were normal, as seen in anorexia nervosa, suggesting that the hypothalamic~ituitary-adrenal axis in these two states is intact . The prolongation of cortisol half-life (50 to 100 percent) suggests decreased metabolic turnover which may explain the decreased excretion of metabolic products in the urine (24) . ACTH secretion has been studied in anorexia nervosa and an absence of the usual pulsatile secretion noted (18, 25) . It is not known whether this is noted in other etarvational states . The stimuli to ACTH secretion are so many and complex that it is impossible to speculate, on the basis of these observations, as to the source of the hyperaecretion seen in anorexia nervosa . The recent report by Krieger et aZ . (26) that ACTH secretion in patients with Cushinq's disease of hypothalamic origin can be suppressed by aypoheptadine directs attention to possible serotonergic hyperactivity in anorexia nervosa, but no data exist on this point. Growth Hormone Both anorexia nervosa patients aad those with protein-caloric malnutrition of other causes may have increased fasting grcvth hormone levels, although retaining normal glucose suppression and normal response to arginine infusion and insulin-induced hypoglycemia (27, 28) . Smith et aZ . studied 17 adult patients with severe malnutrition in a Calcutta hospital before and after refeeding . In a malnourished state the mean fasting serum growth hormone was elevated to 19 .6 t 3 .5 ng/ml~ when the patients had been restored to a good nutritional . status, the fasting growth hormone level fell to a normal range value of 3 .8 t .05 ng/ml (29) . In anorexia nervosa quite comparable values were found by Gârfinkel et at . (21) who studied five adults with anorexia nervosa who were "undernourished" and four who were "well-nourished ." The first group had significantly higher fasting growth hormone levels (20 .2 t 10 .1 nq/ml), while the send group had essentially normal levels (1 .15 t 0 .5 nq/ml) . The elevation of growth hormone levels in both starvation and anorexia nervosa suggests a hyperexcretion for what are now unknown reasons . Growth hormone secretion is felt to be mediated through both alpha- and beta-adrenergic receptor mechanisms with the former stimulatory and the latter inhibitory (30) . Beta Mockers prevent a growth hormone response to insulin-induced hypoglycemia or to arginine infusion, a situation not present in anorexia nervosa or in starvation . Levodopa and apo®orphine, a dopamine agoniat, have been found to stimulate growth hormone release (30) . This levodopa response is not blocked by dopamine beta hydroxylase inhibitors suggesting that norepinephrine ie not involved but that growth hormone is under dopaminergic control . Thus, in anorexia nervosa and in chronic starvation, increases in growth hormone levels may reflect increased dopamine activity at hypothalamic centers . Prolactin In contrast to increased levels of growth hormone and cortisol found in anorexia nervosa, the third hormone usually increased by "stress," prolactin, has been found to be normal in four out of five patients studied by Mecklenberg
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et al . (20) . The other patient did have increased prolaotin and galaotorrhea but had a normal suppression to levodopa . Gonadotre~in Abnormalities of gonadotropic secretion have long been of interest in anarezia nervosa due to the prominence of menstrual dysfunction in women patients . Salmi (7) in an analysis of 62 women with anorexia nervosa, found amenorrhea ocaurying !or various lengths of time in 56 patients who had had menarche by the onset of the illness . Tn 52 percent of these patients menses stopped with the patient's refusal to eats in 21 percent menses ceased prior to food refusal and in 18 percent menses ceased about there months after onset of symptame . That menses in 21 percent of the patients stopped prior to weight lose (or 25 percent in the series of Kay and Leigh (31)), suggests that although menstrual abnormalities can occur in starvation, this is not the explanation in many cases of anorexia nervosa . Although women patients have been most extensively studied, analogous changes have been found in men. As there is decreased saran estrogen in women (20, 25), there is decreased serum testosterone in men (21, 32) . Total urinary gonadotropins are decreased in both sexes, with serum LH more affects than FSH (23, 32), suggesting that decreased pituitary stimulation leads to the decreased estrogen or testosterone . Yet several authors have shown (32, 33, 3d) that the pituitary response to gonadotropin releasing hormone (GnRB) is normal in patients with anorexia nervosa, implying that the problem is above the pituitary is the hypothalamus . Additional evidence for hypothalamic dysfunction comas from studie~ (35) showing that amenorrheic women in the cachectic phase of anorexia nervosa are unresponsive to clamiphena citrate, which acts to increase gonadotropin secretion by blocking the feedback mechanisms of estrogens on the hypoth.i .~,"++p . This was only partly corrected bY releasing eaoe patients with anorexia nervosa . Boyar et aZ.. (36) have shown a regression of nocturnal spiking pattern of Iii in women with anorexia nervosa to an "immature" LS pattern . This pattern matures with refeeding, but may remain abnormal even after weight gain. The control of gonadotropin secretion by neurotransmitters is man remains unclear . In animals all three of the monoaminergic systems appear to be involved (37) . 7n man, however, only the dopaminergic system has been eztnneively studied, and no dopaminergic agonist has ever been shown to have direct effects on gonadotropin levels (38, 39) . At present there is also no convincing documentation of eerotonin or aorepinephrine effects of gonadotropin aecration in humans (30) . Vasopressin _(ADS) Secretion Mecklenburq et 4Z . studied five patients with anorexia nervosa and found four of them to have partial diabetes insipidus (20) .. These patients wind achieve some urinary wncentration after dehydration, but showed further in creases in urine wacentration after exogenous vasopressin (ADS) . This suggests a hypothalamic dysfunction related to AD8 secretion . The role of asurotransmitters in ADH secretion in man ie not understood, although the production of inappropriate ADH secretion by phanothiazinea and the blockage of AD8 secretion by dilantin suggest~ that some or all of the monoaminergic systems may aot'as modulators of neurohypophyseal function .
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Cholesterol Metabolism Hyparcholesterolemia in anorexia nervosa was originally noted by 1Clinefelter (40) anS has been confirnad by aerveral authors (10, 41) . Low serum cholesterol levels would usually be expected in malnourished patients . Attempts to correlate increased serum cholesterol with diet abberations in anorexia nervosa have not been successful . Crisp et al . (42) could not correlate the elevated cholesterol levels in anorexia nervosa with any abnormality of thyroid function . Possible hypothalamic involvement is suggested by reports of hypercholes= . terolemia after combined ventramedial and ventrolateral hypothalamic destruction in adult rate fed low or high cholesterol diets (43, 44) . The precise mecha niema for the developaent of hypercholesterolemia after such lesions is not known . (~tstein et aZ . (45) demonstrated that in rats rises in serum cholesterol followed stimulation of the lateral hypo+h.i~+" and were related to a transient obstructive action on the biliary-duodenal system . Nester (41), studying cholesterol metabolism in patients with anorexia nervosn,~found evidence of obstruction to biliary flow, with marked reduction of bile acid secretion and retention of dietary cholesterol . Although Nestel felt this to be a peripheral effect, the apparently analogous changes in animal studies with hypothalamic stimulation raises the posaiblilty that the hypercholasterolemia in anorexia nervosa may also be related to changes in the hypothalamus . Neurotransmitter regulation of cholesterol metabolism is not clear . Anorexia The involvement of the hypothalamus in regulating feeding is demonstrated bY numerous animal experiments involving destruction or stimulation of hypo+halam_a c centers with resulting hyperphagia or anorexia . Hyparthalamic syn drames including hyperphagia or with anorexia also are wall known is man (15) . Although neurotransmitter rations in anorexia nervosa with regard to anorexia have not been studied, it is clear that increased dopaminergic activity in man will elicit anorexia . The acute effect of amphetamine in producing anorexia is well known . Levodopa in parkinaonism has bean noted to produce a ohronic anorexia unrelated to nausea and vomiting . Cole (46) in reviewing the studies on hypothalamic feeding mechanises, postulates a ventroaiedial "satiety center" and a lateral hypothalamic "feeding center" and suggests that catecholamines act at both centers in producing anorexia . Haez (47) concurs, i~icating that the data point strongly to the involvement of brain catecholamines in the dapraseion of food intake with dopamine-containing neurons playing the major role . Harzaghi et at . (48) observed a reduction of food intake mediated by apomorphine . Apa®orphine is felt to act as a direct dopaminergic agonist with no effect on norapinephrina receptors . The anorexic effect of apomorphine is blocked by pimozide, a dopamine receptor agonist (49) . Thermoregulation Abnormal thermorequlation in anorexia nervosa patients has been daoonstrated by several authors (20, 25, 50) . Meckleaberq et al., studying five patients with anorexia nervosa, found all five, including one patient in clinical remission, to have abnormalities of thereoregulation . Control patients were thin "normale ." The patients with anorexia nervosa did not respond to cold with vasoconstriction or shivering . All five had a decrease in core temperature over 30 minutes, instead of the normal alight rise in temperature, and none was able to stabilise her temperature . In response to heat exposure the initial physiologic decrease in core temperature wan equivocal or absent . Four of the patients had greater than normal increases in core temperature .
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Only one (the patient in clinical remission) had a normal rate of sweating . Mecklenberq et aZ . félt that the failure of patients with anorexia nervosa to respond to hypothermia constituted strong evidence for hypothalamic dysfunction . The neurotransmitter control of thermorequlation in humans is poorly understood . In part this is due to the major differences that appear to exist among reactions of different species of animals to various neuroleptic drugs : attempts to generalize from results of rat or cat experiments to humans can thus be only speculative . However, data obtained in monkeys and baboons (51, 52, 53, 54) clearly implicate the anterior preoptic region of the hypothalamus as temperature sensitive in that waxminq this area with a thermal probe causes the animals to display cutaneous vasodilation and panting -- the responses of heat lose -- even in cold ro~s~ conversely, cooling the temperature-sensitive areas causes prompt vasoconstriction, shivering, and increases in nonshiverinq the=mogeneais, which may be prevented with a peripheral sympathetic blocking agent like trimethaphan (53) . Microinjectiona of serotonin in this area causes thermogenesis with a rise in the rectal temperature of the animal (51) . Injection of norepinephrine in the same region causes heat loss, or occasionally, feeding behavior, but rarely both at precisely the same site (52) . Dopamine is not clearly implicated in the thermoregulatory mechanisms of nonhuman primates (53), though ample data in mice (55) and rats (56) suggests that it promotes heat loss directly or indirectly by increasing cutaneous vaso~ dilation . Blatteis et aZ . (57) have reported that six children with treated or untreated phenylketonuria, who presumably have decreased availability of dopamine and norepinephrine in the central nervous system, fail to perspire normally in a hot environment and eo cannot maintain body temperature at normal levels despite normal vasodilation responses . They speculate that norepinephrine may be a key mediator of sweating in humans although dopamine could just as easily be the catecholamine of major importance . Lovett-Doust et al . (58) studied a group of seven schizophrenic patients who were treated with either MAO-inhibitors alone (to increase central nervous system catecholamines) or Mf~inhibitors plus ß-tryptophan (to increase central nervous system serotonin) . They observed a decline in basal body temperature of about ~oF on the MAOI reigmen and a rise of the same magnitude when tryptophan was added . Thus it appears that in man, as in monkeys, norepinephrine or dopamine may be involved in heat loss and serotonin in thermogenesis . Cranston et aZ . (59) found that chlorpromazine, at doses of 30 mg/day which caused no other physiologic effects in their volunteers, caused marked impairment of hunt loss ha judged by the rate of change of earlobe or oral temperature when the subject was exposed to a hot environment . On the basis of these observations, one might expect that patients treated with neuroleptice would, under proper circumstances, develop spectacular disturbances of thermorequlation (60) . The polypharmacy involved in moat such cases of drug-related heatstroke makes it difficult to implicate blockade of any particular neurotransmitter in the pathogenesis, although the dopaminergic blockade is the most attractive culprit . The above data raises the possibility that dopamine plays a role in heat loss and lowering of body temperature and that increased dopamine activity in the hypothalamus could account for the hypothermia seen in anorexia nervosa . The Pathophys i ology of Anorexia Nervosa Haled on a thorough review of the possible mechanism of the major symptoms, Harry and Klawana (17) have suggested that increased activity of dopamine at
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central dopamine receptors plays a major role in the pathophyaiology of anorexia nervosa . While either dopamine receptor site hypersensitivity or synthesis of a false transmitter could produce the necessary dysfunction, they proposed that a defect in the negative feedback control of dopamine turnover was more consistent with the known features of amrexia nervosa. No other theories of pathophysiology per se have been presented. In summary, in anorexia nervosa . there appears now to be good evidence of hypothalamic dysfunction which is independent of the malnutritional state . This dysfunction involves the regulation of gonadotropin, ACTH, ADH, and, possibly, of growth hormone. In addition there is evidence that abnormalities of cholesterol metaboliam,food intake, and thermorequlation seen in anorexia nervosa may well reflect an abnormality of hypothalamic function . The presence of both psychiatric and hypothalamic dysfunction in anorexia nervosa auggerts that an abnormality of neurotransmitter regulation may be common to both . Unfortunately neurotransmitter regulation of the hypothalamus in man is incompletely understood . At present it appears that dopamine may play a role in the pathophysiology of most of the major symptoms of anorexia nervosa. Acknowled~enta This research was supported in part by grants from the United Parkinson Foundation and the Michael Reese Research Institute Council, Chicago, Illinois . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 .
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T . S . DANOÜSKI, E . LIVSTONE, A . R . GONZALE3, Y . JUNG, and R . C . 1Q~lURANA, Hornanes _3 105-118 (1972) . J . N . C . OOOKE, V . H . T . JAMES, J . IAt~i, and V . WYNN, _Hr . Med . _J . _1 662-666 (1964) . R . J . FRANKSL, and J . S . JENRINS, Acts Endocrinol . (Kbh .) _78 209-221 (1975) . D . T . RRIEGSR, L . AMOROSA, and F . LINICK, N . Sngl . J . Med . 29 3 893-896 (1975) . V . MARKS, N . HOWOFà1H, and F . C . GRBSNWOOD, Nature _208 686-687 (1965) . T . J . MERIMEE, and S . S . FTxume>zs , _J . Clin . Endocrinol . Metab . _39 385386 (1974) . 3 . R . SMITH, P . J . EDGAR, T . POZEFSRY, M . K . CHSSTRI, and T . E . PROUT, _J . Clin . Brtdocrinol . Metab . _39 53-62 (1974) . L . A. FROHMAN, and M . E . STACHURA, Metabolism _24 211-234 (1975) . D . W . K . KAY, and D . LEIGH, J_ . Ment . 8ci . _100 411-431 (1954) . K . A. HALMI, and B . M . SHSRMAN, Arch . Gea . Psychiatry _32 875-878 (1975) . W . WIBGSI~9tNN, and H . G . SOLHACH, Horm . Metab . Res . _4 404 (1972) . C . H . MDRTIMER, G . M . BESSER, R. FISHER, and A . S . MC NEILLY, paper read at the 56th Annual Meeting of the Endocrine Society , Atlanta, Georgia (June 1974) . J . C . MARSHALL, and T . R . FRASER, _Br . Med . _J . 4 590-592 (1971) . R . M . BOYAR, J . KATZ, J . W . FIN103LSTSIN, S . KAPEN, H . WEIHER, F . D . WEITZMAN, and L . saxr "r"~x , _N . Bngl . J . Med . _291 861-865 (1974) . S . M . MC CANN, P . S . KALRA, A . O . DONO80, W . BISHOP, H . P . G . SCHNSIDER, C . P . FAWCÉIT, and L . KRULICH, Brain-Endocrine Interaction . Median éminence : Structure artd Function ,pp .224-235 Karqer, Basel (1972) . R. L . EDDY, A . L . JONES, Z . H . CHA1Q41147IAN, and M. C . SILVERTHORäB, _J . Clin . Endocrinol . Metab . _33 709-712 (1971) . S . B . SINHa1MAHAPATRA, and M . A . KIRSCE~iER, J . Clin . Endocrinol . Metab . _34 756-758 (1972) . H . F . tcr "r~rnaar .mizu , _J . Clin . Sndocrinol . Metab . _25 1520-1521 (1965) . P . J . :~.~^°..:. , _J . Clin . Sadocrinol . Metab . _38 324-328 (1974) . A . H . CRISP, L . M . BLHNDIS, and G . L . S . PAWAN, Metabolism 17 1109-1112 (1968) . M. FRISDt~lAN, S . O . BYERS, and S . R. ELSR, Proc . Soc . ~t . Biol . Med . 131 759-762 (1969) . L . L . HEIttiARDIS, and J . D . 3CHNATZ, J . Neuro-Visveral Rel . 32 90-94 (1971) . W . H . GUTSTEIN, D . J . SCSNSCR, and H.APPLETON, Metabolism _18 300-310 (1969) . S . O . COLS, Psychol . Hull . _79 13-20 (1973) . L . A . BAEZ, PeychopYtaxmacologia _35 91-98 (1974) . F . BARZAGHI, A . GRpPPE'1TI, P . MANPSGAZZA, and E . F, urir"Taxa , J . Pklarm . Pharmacol . _25 909-911 (1973) . A . M . ERNST, Psyckwpharmacologia _10 316-323 (1967) . A . WAKELING, and G, F . M . RUSSBTd., Psychol . Med . _1 30-39 (1970) . R . D . MYERS, and M . B . WALLSR, Brain Res . _84 47-61 (1975) . T . L . MARSH, and R. D . MYERS, Physiol . Behav . 8 251-257 (1972) . C . C . GALS, and P . TOIVOLA, Hormones _1 164-192(1970) . G . H . HALL, and R . D . MYSRS, Braia Res . _37 241-251 (1973) . K . Y . 8 . LA(~RSPETZ, R. TIRRI, H . TAR1a00d~N, and H . JALKU, Med . Biol . _52 181-188 (1974) . B . R . COOPER, and G . R . BR88SE, Neuropsychopharmaoology of Mostoaminas and Their Regulatory Enzymes , pp . 353-368 Raven Press, New York (1974) . C . M . BLATTEIS, G . J . HILT~SIBR, and T . M . GILBERT, Padiatr . Res . _8 809-814 (1974) . J . W . LOVERT-DOUST, L . HUSZKA, and M . LITTLE, Int . Pharmacopsychiatry _8 239-244 (1973) . W . CRANSTON, T . FOLSY, R . LUFF, and M . RAWLINS, Br . _J . Pharmacol . _43 555556 (1972) . D . REIMER, J . MOHAN, and S . NAGASWAMI, J . Fla . Med . Aseoc . 6 1 573 (1974) .
Pergamoa Press
MINIREVIEiP BIOIAGICAL ASPECTS OF AMORESIA NBRVOSA Mark Lupton, Laura Simoa, Virginia Harry, and Harold L . 1Clawana Divisions of Neurology and Endocrinology, Department of Medicine, and the Psychosomatic and Psychiatric Institute, Michael Reese Hospital and Medical Center, Chicago, Illinois 60616 Anorexia nervosa has been recognized as a distinct disorder for yell over a hundred years . Originally described in 1868 by Gull (1) in England and in 1873 by Laségue (2) in France, this disease continues to puzzle with its peculiar combination of paychological and physiological manifestations . Since refusal to eat may occur in various physiologic or psychiatric diseases other than anorexia nervosa, the differential diagnosis is sometimes complicated . Current published criteria (3) res++ir e (A)
Aqe of onset prior to 25
(H)
Anorexia with accompanying weight loss of at least 25 percent of original body weight
(C)
A distorted implacable attitude towards eating, food, or weight that overrides hunger, admonitions, reassurance and threats, e .g ., (1) denial of illness with a failure to recognise nutritional needs, (2) apparent enjoyment in losing weight with overt manifestations that food refusal ie a pleasurable indulgence, (3) a desired body image of eztrenn thinness with overt evidence that it is rewarding to the patient to achieve and maintain this state, and (4) unusual hoarding or handling of food
(D)
No known medical illness that could account for the anorexia and weight loss
(E)
At least two of the following manifeatationes (1) amenorrhea, (2) laaugo, (3) bradycardia (persistent resting pulse of 60 or leas), (4) periods of overactivity, (5) episodes of bulimia, or (6) vomiting (this may be self induced) .
It should ba noted that men as well as women may develop anorexia nervosa . This was noted by Gull (4) in his more extensive 1874 description, but aubssquaat focusing on the symptom of amenorrhea as a key diagnostic feature distracted attention from hale patients with a similar syndrome, but, of course, without amenorrhea . There is now good agreement with Gull that males may alw have anorexia nervosa (5, 6, 7) . Tha average annual incidence of anorexia nervosa is estimated at being 0 .24 to 0 .61 cases par 100,000 population (8) . üomea are affected about 10 to 20 times more frequently than nen (7) . The average age of onset is prior to age 25, with rare cases being reported before age 10 (9) or after age 40 (10) . The prognosis for recovery is generally related to aqa of onset, with poat~ubertal adolescents tending to be most asverely affected . The incidence of mortality rangea from five percent (11) to 20 percent (10, 1341
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12) . Seidensticker and Tzaqournia presented a series of 60 patients hospitalized with anorexia nervosa and followed for up to ten years (10) . Sixty eight percent were either "satisfactory" (i .e ., essentially normal) or "partially satisfactory," 14 percent were "unsatisfactory," and 17 percent had died of malnutrition, intercurrent infection, suicide, or other miscellaneous causes . Curiously, various treatment schedules, including combinations of psychotherapy, drug therapy, tube feedings, and prolonged hospitalizations had equal success. Gull noted in his original description that spontaneous remission often occurs if supportive nutritional therapy can be continued. over months or years (4) . The central clinical problem in anorexia nervosa is weight lose . Patients with anorexia nervosa can lose more than 50 percent of their original body weight (10) . Many of the physical manifestations of anorexia nervosa, including pallor, relative hypotension, bradycardia, leukopenia, dry skin, lanugo hair, abnormalities of glucose tolerance tests, and constipation may be manifeatationa of generalized malnutrition (13, 14), and need not be related to the pathophysiology of anorexia nervosa per se . There are, however, a variety of metabolic changes which would suggest a wide-spread hypothalamic dysfunction in anorexia nervosa . This association of anorexia nervosa with hypothalamic dysfunction is supported by the observation of occasional cases of hypothalamic tumors presenting with anorexia nervosa-like symptoms (15, 16) . It is the purpose of this report to review whether there is evidence that the metabolic disturbances in anorexia nervosa may be related to a hypothalamic dysfunction which is not simply a result of malnutrition . The coexistence of both a psychiatric disturbance and of a separate hypothalamic dysfunction suggests an underlying neurotransmitter abnormality that would be common to both types of dysfunction (17) . The metabolic disturbances of anorexia nervosa are primarily hypothalamic . The traditional hypothalamicrpituitary-end organ relationships will first be reviewed and then other nonrpituitary hypothalamic functions . Thyro id Function Patients who are severely malnourished, whether fry anorexia nervosa or Thus 20 from starvation, often have a characteristic hypoa~etabolic state. percent of Warren and Vende Wiele's patients with anorexia nervosa had a low calculated basal metabolic rate (18) . Keys et al . also noted low basal metabolic rates to be present in patients with malnutrition but without anorexia nervosa (13) . This hypometabolic state resembles myxedema (a disease also described by Gull) and led to many investigations of thyroid metabolism in patients with anorexia nervosa, although their hyperactivity would suggest that they are anything but hypothyroid. Thyroid function studies have in fact been uniformly normal (18, 19, 20, 21) . These include PBI, TBG, T4 , T3~ resin uptake, RAI uptake . A low serum thyroxine by column has been noted, but this has also been noted in chronically ill patients (22) . Adrenal Function Anorexia nervosa has also been compared with hypoadrenalism . Patients with anorexia nervosa have often been reported to have low urinary 17-ketosteroids, and, less often, to have low 17-hydroxycorticoids . Thus five of eight patients studied by Garfinkel et aZ . (21) had below normal urine 17ketosteroids, although all had normal 17-hydroxycorticoida . Danowski et al . (23) found low urinary 17-ketosteroida in six of 16 (31 percent) patients, and Warren and Vende Wiele found low 17-ketosteroids in 18 of 42 patients (42 percent with anorexia nervosa (18)). Despite this finding of low 17-ketosteroids in the urine, which in usual circumstances denotes hypoadrenaliam, these same
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authors have found normal or paradoxially elevated levels of plasma cortisol . Comparisons with other starvation states suggest that these changes are not unique to anorexia nervosa . Cooks et aZ . (24) studied 33 patients with chronic malnutrition in comparison with 96 patients who were "normal" nourished . The starved patients had a low 24 hour urine 17-ketoateroid, an impaired urinary 17-ketosteroid and 17-hydroxycorticoid response to ACTH, sad a delayed rate of disappearance of cortisol from the plasma . In these patients both the resting plasma cortisol level and adrenocortical response to acute hypoglycemic stress were normal, as seen in anorexia nervosa, suggesting that the hypothalamic~ituitary-adrenal axis in these two states is intact . The prolongation of cortisol half-life (50 to 100 percent) suggests decreased metabolic turnover which may explain the decreased excretion of metabolic products in the urine (24) . ACTH secretion has been studied in anorexia nervosa and an absence of the usual pulsatile secretion noted (18, 25) . It is not known whether this is noted in other etarvational states . The stimuli to ACTH secretion are so many and complex that it is impossible to speculate, on the basis of these observations, as to the source of the hyperaecretion seen in anorexia nervosa . The recent report by Krieger et aZ . (26) that ACTH secretion in patients with Cushinq's disease of hypothalamic origin can be suppressed by aypoheptadine directs attention to possible serotonergic hyperactivity in anorexia nervosa, but no data exist on this point. Growth Hormone Both anorexia nervosa patients aad those with protein-caloric malnutrition of other causes may have increased fasting grcvth hormone levels, although retaining normal glucose suppression and normal response to arginine infusion and insulin-induced hypoglycemia (27, 28) . Smith et aZ . studied 17 adult patients with severe malnutrition in a Calcutta hospital before and after refeeding . In a malnourished state the mean fasting serum growth hormone was elevated to 19 .6 t 3 .5 ng/ml~ when the patients had been restored to a good nutritional . status, the fasting growth hormone level fell to a normal range value of 3 .8 t .05 ng/ml (29) . In anorexia nervosa quite comparable values were found by Gârfinkel et at . (21) who studied five adults with anorexia nervosa who were "undernourished" and four who were "well-nourished ." The first group had significantly higher fasting growth hormone levels (20 .2 t 10 .1 nq/ml), while the send group had essentially normal levels (1 .15 t 0 .5 nq/ml) . The elevation of growth hormone levels in both starvation and anorexia nervosa suggests a hyperexcretion for what are now unknown reasons . Growth hormone secretion is felt to be mediated through both alpha- and beta-adrenergic receptor mechanisms with the former stimulatory and the latter inhibitory (30) . Beta Mockers prevent a growth hormone response to insulin-induced hypoglycemia or to arginine infusion, a situation not present in anorexia nervosa or in starvation . Levodopa and apo®orphine, a dopamine agoniat, have been found to stimulate growth hormone release (30) . This levodopa response is not blocked by dopamine beta hydroxylase inhibitors suggesting that norepinephrine ie not involved but that growth hormone is under dopaminergic control . Thus, in anorexia nervosa and in chronic starvation, increases in growth hormone levels may reflect increased dopamine activity at hypothalamic centers . Prolactin In contrast to increased levels of growth hormone and cortisol found in anorexia nervosa, the third hormone usually increased by "stress," prolactin, has been found to be normal in four out of five patients studied by Mecklenberg
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et al . (20) . The other patient did have increased prolaotin and galaotorrhea but had a normal suppression to levodopa . Gonadotre~in Abnormalities of gonadotropic secretion have long been of interest in anarezia nervosa due to the prominence of menstrual dysfunction in women patients . Salmi (7) in an analysis of 62 women with anorexia nervosa, found amenorrhea ocaurying !or various lengths of time in 56 patients who had had menarche by the onset of the illness . Tn 52 percent of these patients menses stopped with the patient's refusal to eats in 21 percent menses ceased prior to food refusal and in 18 percent menses ceased about there months after onset of symptame . That menses in 21 percent of the patients stopped prior to weight lose (or 25 percent in the series of Kay and Leigh (31)), suggests that although menstrual abnormalities can occur in starvation, this is not the explanation in many cases of anorexia nervosa . Although women patients have been most extensively studied, analogous changes have been found in men. As there is decreased saran estrogen in women (20, 25), there is decreased serum testosterone in men (21, 32) . Total urinary gonadotropins are decreased in both sexes, with serum LH more affects than FSH (23, 32), suggesting that decreased pituitary stimulation leads to the decreased estrogen or testosterone . Yet several authors have shown (32, 33, 3d) that the pituitary response to gonadotropin releasing hormone (GnRB) is normal in patients with anorexia nervosa, implying that the problem is above the pituitary is the hypothalamus . Additional evidence for hypothalamic dysfunction comas from studie~ (35) showing that amenorrheic women in the cachectic phase of anorexia nervosa are unresponsive to clamiphena citrate, which acts to increase gonadotropin secretion by blocking the feedback mechanisms of estrogens on the hypoth.i .~,"++p . This was only partly corrected bY releasing eaoe patients with anorexia nervosa . Boyar et aZ.. (36) have shown a regression of nocturnal spiking pattern of Iii in women with anorexia nervosa to an "immature" LS pattern . This pattern matures with refeeding, but may remain abnormal even after weight gain. The control of gonadotropin secretion by neurotransmitters is man remains unclear . In animals all three of the monoaminergic systems appear to be involved (37) . 7n man, however, only the dopaminergic system has been eztnneively studied, and no dopaminergic agonist has ever been shown to have direct effects on gonadotropin levels (38, 39) . At present there is also no convincing documentation of eerotonin or aorepinephrine effects of gonadotropin aecration in humans (30) . Vasopressin _(ADS) Secretion Mecklenburq et 4Z . studied five patients with anorexia nervosa and found four of them to have partial diabetes insipidus (20) .. These patients wind achieve some urinary wncentration after dehydration, but showed further in creases in urine wacentration after exogenous vasopressin (ADS) . This suggests a hypothalamic dysfunction related to AD8 secretion . The role of asurotransmitters in ADH secretion in man ie not understood, although the production of inappropriate ADH secretion by phanothiazinea and the blockage of AD8 secretion by dilantin suggest~ that some or all of the monoaminergic systems may aot'as modulators of neurohypophyseal function .
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Cholesterol Metabolism Hyparcholesterolemia in anorexia nervosa was originally noted by 1Clinefelter (40) anS has been confirnad by aerveral authors (10, 41) . Low serum cholesterol levels would usually be expected in malnourished patients . Attempts to correlate increased serum cholesterol with diet abberations in anorexia nervosa have not been successful . Crisp et al . (42) could not correlate the elevated cholesterol levels in anorexia nervosa with any abnormality of thyroid function . Possible hypothalamic involvement is suggested by reports of hypercholes= . terolemia after combined ventramedial and ventrolateral hypothalamic destruction in adult rate fed low or high cholesterol diets (43, 44) . The precise mecha niema for the developaent of hypercholesterolemia after such lesions is not known . (~tstein et aZ . (45) demonstrated that in rats rises in serum cholesterol followed stimulation of the lateral hypo+h.i~+" and were related to a transient obstructive action on the biliary-duodenal system . Nester (41), studying cholesterol metabolism in patients with anorexia nervosn,~found evidence of obstruction to biliary flow, with marked reduction of bile acid secretion and retention of dietary cholesterol . Although Nestel felt this to be a peripheral effect, the apparently analogous changes in animal studies with hypothalamic stimulation raises the posaiblilty that the hypercholasterolemia in anorexia nervosa may also be related to changes in the hypothalamus . Neurotransmitter regulation of cholesterol metabolism is not clear . Anorexia The involvement of the hypothalamus in regulating feeding is demonstrated bY numerous animal experiments involving destruction or stimulation of hypo+halam_a c centers with resulting hyperphagia or anorexia . Hyparthalamic syn drames including hyperphagia or with anorexia also are wall known is man (15) . Although neurotransmitter rations in anorexia nervosa with regard to anorexia have not been studied, it is clear that increased dopaminergic activity in man will elicit anorexia . The acute effect of amphetamine in producing anorexia is well known . Levodopa in parkinaonism has bean noted to produce a ohronic anorexia unrelated to nausea and vomiting . Cole (46) in reviewing the studies on hypothalamic feeding mechanises, postulates a ventroaiedial "satiety center" and a lateral hypothalamic "feeding center" and suggests that catecholamines act at both centers in producing anorexia . Haez (47) concurs, i~icating that the data point strongly to the involvement of brain catecholamines in the dapraseion of food intake with dopamine-containing neurons playing the major role . Harzaghi et at . (48) observed a reduction of food intake mediated by apomorphine . Apa®orphine is felt to act as a direct dopaminergic agonist with no effect on norapinephrina receptors . The anorexic effect of apomorphine is blocked by pimozide, a dopamine receptor agonist (49) . Thermoregulation Abnormal thermorequlation in anorexia nervosa patients has been daoonstrated by several authors (20, 25, 50) . Meckleaberq et al., studying five patients with anorexia nervosa, found all five, including one patient in clinical remission, to have abnormalities of thereoregulation . Control patients were thin "normale ." The patients with anorexia nervosa did not respond to cold with vasoconstriction or shivering . All five had a decrease in core temperature over 30 minutes, instead of the normal alight rise in temperature, and none was able to stabilise her temperature . In response to heat exposure the initial physiologic decrease in core temperature wan equivocal or absent . Four of the patients had greater than normal increases in core temperature .
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Only one (the patient in clinical remission) had a normal rate of sweating . Mecklenberq et aZ . félt that the failure of patients with anorexia nervosa to respond to hypothermia constituted strong evidence for hypothalamic dysfunction . The neurotransmitter control of thermorequlation in humans is poorly understood . In part this is due to the major differences that appear to exist among reactions of different species of animals to various neuroleptic drugs : attempts to generalize from results of rat or cat experiments to humans can thus be only speculative . However, data obtained in monkeys and baboons (51, 52, 53, 54) clearly implicate the anterior preoptic region of the hypothalamus as temperature sensitive in that waxminq this area with a thermal probe causes the animals to display cutaneous vasodilation and panting -- the responses of heat lose -- even in cold ro~s~ conversely, cooling the temperature-sensitive areas causes prompt vasoconstriction, shivering, and increases in nonshiverinq the=mogeneais, which may be prevented with a peripheral sympathetic blocking agent like trimethaphan (53) . Microinjectiona of serotonin in this area causes thermogenesis with a rise in the rectal temperature of the animal (51) . Injection of norepinephrine in the same region causes heat loss, or occasionally, feeding behavior, but rarely both at precisely the same site (52) . Dopamine is not clearly implicated in the thermoregulatory mechanisms of nonhuman primates (53), though ample data in mice (55) and rats (56) suggests that it promotes heat loss directly or indirectly by increasing cutaneous vaso~ dilation . Blatteis et aZ . (57) have reported that six children with treated or untreated phenylketonuria, who presumably have decreased availability of dopamine and norepinephrine in the central nervous system, fail to perspire normally in a hot environment and eo cannot maintain body temperature at normal levels despite normal vasodilation responses . They speculate that norepinephrine may be a key mediator of sweating in humans although dopamine could just as easily be the catecholamine of major importance . Lovett-Doust et al . (58) studied a group of seven schizophrenic patients who were treated with either MAO-inhibitors alone (to increase central nervous system catecholamines) or Mf~inhibitors plus ß-tryptophan (to increase central nervous system serotonin) . They observed a decline in basal body temperature of about ~oF on the MAOI reigmen and a rise of the same magnitude when tryptophan was added . Thus it appears that in man, as in monkeys, norepinephrine or dopamine may be involved in heat loss and serotonin in thermogenesis . Cranston et aZ . (59) found that chlorpromazine, at doses of 30 mg/day which caused no other physiologic effects in their volunteers, caused marked impairment of hunt loss ha judged by the rate of change of earlobe or oral temperature when the subject was exposed to a hot environment . On the basis of these observations, one might expect that patients treated with neuroleptice would, under proper circumstances, develop spectacular disturbances of thermorequlation (60) . The polypharmacy involved in moat such cases of drug-related heatstroke makes it difficult to implicate blockade of any particular neurotransmitter in the pathogenesis, although the dopaminergic blockade is the most attractive culprit . The above data raises the possibility that dopamine plays a role in heat loss and lowering of body temperature and that increased dopamine activity in the hypothalamus could account for the hypothermia seen in anorexia nervosa . The Pathophys i ology of Anorexia Nervosa Haled on a thorough review of the possible mechanism of the major symptoms, Harry and Klawana (17) have suggested that increased activity of dopamine at
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central dopamine receptors plays a major role in the pathophyaiology of anorexia nervosa . While either dopamine receptor site hypersensitivity or synthesis of a false transmitter could produce the necessary dysfunction, they proposed that a defect in the negative feedback control of dopamine turnover was more consistent with the known features of amrexia nervosa. No other theories of pathophysiology per se have been presented. In summary, in anorexia nervosa . there appears now to be good evidence of hypothalamic dysfunction which is independent of the malnutritional state . This dysfunction involves the regulation of gonadotropin, ACTH, ADH, and, possibly, of growth hormone. In addition there is evidence that abnormalities of cholesterol metaboliam,food intake, and thermorequlation seen in anorexia nervosa may well reflect an abnormality of hypothalamic function . The presence of both psychiatric and hypothalamic dysfunction in anorexia nervosa auggerts that an abnormality of neurotransmitter regulation may be common to both . Unfortunately neurotransmitter regulation of the hypothalamus in man is incompletely understood . At present it appears that dopamine may play a role in the pathophysiology of most of the major symptoms of anorexia nervosa. Acknowled~enta This research was supported in part by grants from the United Parkinson Foundation and the Michael Reese Research Institute Council, Chicago, Illinois . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 .
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