|
The Biological Basis of Anorexia Nervosa
Anorexia nervosa is a serious illness with biological, emotional and behavioral components. The hallmarks of the disorder are excessive weight loss, intense fear of gaining weight, amenorrhea, and cognitive and emotional disturbances in the way body weight and shape are experienced. Most cases of anorexia arise in adolescent and young adult women but the disease also strikes younger children and older adults. The American Psychiatric Association estimates the lifetime prevalence for women as ranging from 0.3% for narrowly defined criteria to 3.7% for broader definitions of the illness (1). With treatment, particularly if this treatment is rendered early in the course of the illness, most patients improve and many recover.
Anorexia nervosa is a disorder of the brain. It is now widely accepted that alterations in neuronal pathways play a role in the etiology of eating disorders. Individuals with anorexia have disturbances in brain serotonin, a neurotransmitter that helps regulate mood, appetite and behavior (2). It is important to note that patients demonstrate serotonin abnormalities not only while they are ill, but also after they have recovered. Researchers often test patients after recovery to determine whether there are remaining deficits in brain function; abnormalities that persist after weight-restoration suggest that they predated the onset of the illness. Serotonin disturbances are believed to contribute to the long-term anxiety, obsessionality, and perfectionism that characterize anorexia (2).
Recent research has also focused on a number of neuropeptides (molecular messengers) that interact with brain cells to regulate appetite and energy release (3). Peptide YY, for example, derives from the gastrointestinal tract and tends to reduce food intake. Levels of PYY are higher in adolescent girls with anorexia nervosa than in healthy controls (4). The peptide hormone ghrelin has been shown to exert significant effects on appetite and is also found in higher concentrations in individuals with anorexia nervosa than in those who do not have the illness (5). Leptin, which is released from the body’s fat cells, is diminished in women with anorexia nervosa compared to healthy controls (6). A growing body of evidence points to changes in neuropeptide activity as involved in the disturbed eating and hormone abnormalities that typify anorexia nervosa (2).
Family studies have been instrumental in teaching us about the genetic aspects of anorexia. Results show that anorexia runs in families (2). Numerous research projects have demonstrated that relatives of individuals with anorexia are more likely to develop the illness than relatives of control subjects (7). Many relatives of people with anorexia or bulimia experience a less severe case of the illness and do not get diagnosed. Twin studies shed further light on the genetics of anorexia. Data collected on a large sample in 1995 found co-twins of individuals with anorexia at significantly higher risk of anorexia nervosa, bulimia nervosa, major depression and low body index than those in families without an eating disorder (8).
Anorexia nervosa is polygenic, meaning that its development is influenced not by a single gene but by the combined effects of many. Over the past 12 years, increasing attention has focused on finding the contributing genes. In order to appreciate the complexities of this challenge, it is helpful to think of the human genome (the entirety of a person’s DNA) as a code of over 3 billion molecular bases across 23 pair of chromosomes (9). Genetic makeup is largely determined by the order in which these bases occur. This sequence is very much the same from one person to another, but there are millions of individual differences along the way that can serve as potential identifiers of disease vulnerability (9). Although scientists have not yet located the precise genes that increase the risk of eating disorders, they are making progress. Research conducted about five years ago pointed to significant genetic activity on chromosomes 1 and 10 for anorexia and bulimia, laying the groundwork for important studies that are now underway (10, 11).
Anorexia nervosa often co-exists with other biologically-based, polygenic mental illnesses such as mood disorders and obsessive compulsive disorder (OCD). For example, it is quite common for patients with anorexia to also suffer from major depression (12). Obsessive-compulsive personality traits in childhood are related to an increased likelihood of adult eating disorders (13). According to the American Psychiatric Association, OCD symptoms are frequently observed in patients with anorexia nervosa who have returned to a healthy weight, and the lifetime prevalence of OCD among those with anorexia is as high as 25% (1).
To put the question of biological basis in perspective, it is helpful to look at what has been reported about the mental illnesses that often accompany eating disorders. Studies of major depression have yielded valuable clues—particularly about neurotransmitter systems—and called attention to several genes as potential contributors to the illness; yet understanding of the neurochemical and genetic underpinnings of major depression is incomplete (14). Serotonin abnormalities have also been implicated in the biology of OCD and though research to identify the specific genes that confer vulnerability to this condition has moved forward, there is still a long way to go (15).
Estimated heritability statistics provide additional perspective on the biological basis of eating disorders. A 2001 investigation attributes more than 50% of the variance in eating disorders and disordered eating behaviors to genetic effects (16). A study conducted in 2006 estimated anorexia’s heritability at 56% (17), which is higher than that of major depression and higher than that of obsessive-compulsive behavior, estimated to be 38% (18) and 36% (19), respectively.
Individuals with anorexia experience problems with attention, concentration, memory, and visuospatial ability; with weight gain, some of these cognitive impairments resolve while others do not (20, 21, 22). Using CT (computerized tomography) and MRI (magnetic resonance imagery), scientists have studied brain structure in patients with anorexia and identified deficits in white matter (filaments that transmit messages between neurons) as well as in gray matter (cell bodies of neurons). With nutrition restoration, these effects are only partially reversible (20, 21, 22).
In 2003, a research team in London examined the brains of patients with early-onset anorexia by single-photon computerized tomography (SPECT) and found irregularities in 11 (73%) of the 15 subjects tested, raising the possibility that the neuronal pathway deficit that characterizes this illness could reside in the limbic system (23). Neuroimaging studies have also demonstrated that patients with anorexia nervosa have reduced blood flow in some regions of the brain as compared to individuals without the disorder (24).
Patients with anorexia nervosa suffer physiological changes which, if untreated, can lead to significant medical problems and, in some cases, death. Anorexia’s mortality rate, reported at 0.56% per year, or about 5.6% per decade, is the highest of any psychiatric disorder and is over 12 times higher than the death rate among young women in the general population (25). A longitudinal study found that 11 of 246 patients had died after 9 years of follow-up and that 4 of these were due to suicide (26).
The most serious complications of anorexia derive from undernutrition. Patients present with muscle wasting, weakness, and low body temperature; their extremities may be cold and blue and their skin yellow or pale. Loss of scalp hair is not unusual. Some patients develop lanugo, soft, fine hair on their trunks and arms. Others complain of bloating or constipation (27).
Of primary concern are electrolyte abnormalities and cardiac arrhythmias. Dehydration may be observed along with abnormal levels of serum sodium, potassium, chloride, carbon dioxide and B.U.N. (27). Individuals with anorexia who vomit or overuse laxatives or diuretics are more prone to electrolyte problems than those who do not engage in these behaviors. Patients who drink very large volumes of water sometimes develop hyponatremia. The combination of hyponatremia and water intoxication lowers the threshold for seizures and coma and can prove fatal (27). Serum phosphorus levels are typically normal when first tested but may fall when nutritional restoration begins; in fact, hypophosphatemia may contribute to “refeeding syndrome,” which is characterized by cardiac arrhythmias and unanticipated death (28).
Patients typically have slow resting pulses and hypotension and some experience dizziness or fainting when they stand up (27). In fact, orthostatic pulse changes have been noted in 60-85% of patients during their first four days of inpatient treatment (29). As many as 75% of adolescents hospitalized for anorexia nervosa demonstrate abnormal electrocardiogram changes (30, 31). An EKG showing a prolonged QTc interval can be a forerunner of ventricular arrhythmia and unforeseen death (32).
Turning now to hematology, bone marrow suppression – low red blood cell, white blood cell, and platelet counts - often accompanies anorexia. Leukopenia (low WBC), noted in one to two thirds of anorectics (30, 33) can increase the time required for infections to heal (27). With nutritional restoration, red cell, white cell and platelet counts generally return to normal (27).
Slowed growth and short stature can occur when young people develop anorexia before they have reached their full height potential (27). Through nutritional replenishment, it is possible for recovering adolescents to make up some of their lost growth; nevertheless, they may never achieve their full growth potential (34).
Amenorrhea (missed menses), one of the defining features of anorexia nervosa, results from poor nutrition, over-exercise, low weight, reduced body fat, and psychological stress (27). The most concerning consequence of amenorrhea and low estrogen is osteopenia (bone loss) which can develop soon after the onset of anorexia (35) and progress to osteoporosis. In a study of 130 young women with anorexia, over 90% showed significant bone loss at one or more skeletal sites, suggesting that women with this disorder are at a significantly increased risk for fracture (36).
Skeletal Architecture in Healthy Young Woman
Photo:Courtesy of MGH Neuroendocrine Unit
Skeletal Architecture in Young Woman with Anorexia Nervosa
Photo:Courtesy of MGH Neuroendocrine Unit
Initiatives are underway on many fronts to improve treatment modalities and to make care accessible to all patients. A multidisciplinary, team approach to treatment is most effective due to the disease’s complex combination of genetic, neurochemical, psychological and sociocultural variables. Patients with severe anorexia require careful medical monitoring and sometimes hospitalization. Clinically indicated services generally include monitoring by a primary care physician; laboratory testing; nutrition counseling; individual, group and/or family psychotherapy; psychopharmacology consult.
It is important to note that discharging patients from the hospital before they have achieved a healthy weight places them at higher risk for relapse and rehospitalization (37, 38). A study conducted in 2000 with a national database indicated that the number of days of care insurance companies cover for an eating disorder falls below the clinically recommended standard (39).
Once a patient with anorexia is medically stable, psychotherapy is clinically necessary in order to help her maintain her hard-won nutritional stability and continue her road to recovery. In essence, psychotherapy can serve as a life-line and effect long-term, positive changes in patients. Cognitive and behavioral models of therapy as well as eclectic, flexible techniques have been effective (40). Family therapy is a key part of treatment for children, adolescents and some adults (41). Comprehensive, individualized and diligently implemented treatment plans save lives and help prevent relapse of this painful and dangerous illness.
Click to view:
The Biological Basis of Bulimia Nervosa
The Biological Basis of Eating Disorder Not Otherwise Specified (EDNOS)
References: The Biological Basis of Anorexia Nervosa
1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Eating Disorders, Third Edition. American Journal of Psychiatry. 2006; 163: 4-54.
2. Kaye, W. Neurobiology of anorexia and bulimia nervosa. Physiology and Behavior. 2007 November 29, [Epub ahead of print].
3. Jimerson, D.D., Wolfe, B.E. Neuropeptides in eating disorders. CNS Spectrums. 2004; 9: 516-22.
4. Misra, M., Miller, K.K., Tsai, P., Gallagher, K., Lin, A., Lee, N., Herzog, D.B.,
Klibanski, A. Elevated peptide YY levels in adolescent girls with anorexia nervosa. Journal of Clinical Endocrinology & Metabolism. 2006; 91:1027–1033.
5. Misra, M., Miller, K.K., Kuo, K., Griffin, K., Stewart, V., Hunter, E., Herzog, D.B., Klibanski, A. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. American Journal of Physiology-Endocrinology and Metabolism. 2005; 289: E347-56.
6. Misra, M., Miller, K.K., Kuo, K., Griffin, K., Stewart, V., Hunter, E., Herzog, D.B., Klibanski, A. Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. American Journal of Physiology-Endocrinology and Metabolism. 2005; 289: E373-81.
7. Lilenfeld, L.R., Kaye, W.H., Greeno, C.G., Merikangas, K.R., Plotnicov, K., Pollice, C., Rao, R., Strober, M., Bulik, C.M., Nagy, L. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first –degree relatives and effect of proband comorbidity. Archives of General Psychiatry. 1998; 55: 603-10.
8. Walters, E.E., Kendler, K.S. Anorexia nervosa and anorexic-like syndromes in a population-based female twin sample. American Journal of Psychiatry. 1995; 152: 64-71.
9. “The New Frontiers of Medicine: Cutting-Edge Research in the Fight against Disease.” Harvard Medical School, 2006.
10. Department of Psychiatry, University of Pittsburgh School of Medicine. A genetic study of anorexia nervosa in families: Why is the NIH funding genetic research into anorexia? http://www.wpic.pitt.edu/research/angenetics/relevant_research.html.
Accessed 4/3/08.
11. Kaye, W.H., Bulik, C.M., Plotnicov, K., Thornton, L., Devlin, B., Fichter, M.M., Treasure, J., Kaplan, A., Woodside, D.B., Johnson, C.L., Halmi, K., Brandt, H.A., Crawford, S., Mitchell, J.E., Strober, M., Berrettini, W., Jones, I. The genetics of anorexia nervosa collaborative study: methods and sample description. International Journal of Eating Disorders. 2008 Jan. 30 [Epub ahead of print].
12. Herzog, D.B., Keller, M.B., Sacks, N.R., Yeh, C.J., Lavori, P.W. Psychiatric comorbidity in treatment-seeking anorexics and bulimics. Journal of the American Academy of Child and Adolescent Psychiatry. 1992; 31: 810-8.
13. Anderluh M.B., Tchanturia, K., Rabe-Hesketh, S., Treasure, J. Childhood obsessive-compulsive personality traits in adult women with eating disorders: defining a broader eating disorder phenotype. American Journal of Psychiatry. 2003; 160: 242-7.
14. Barton, D.A., Esler, M.D., Dawood, T., Lambert, E.A., Haikerwal, D., Brenchley, C., Socratous, F., Hastings, J., Guo, L., Wiesner, G., Kaye, D.M., Bayles, R., Schlaich, M.P., Lambert, G.W. Elevated brain serotonin turnover inpatients with depression: effect of genotype and therapy. Archives of General Psychiatry. 2008; 65: 38-46.
15. Saiz, P.A., Garcia-Portilla, M.P., Arango, C., Morales, B., Bascaran, M.T., Martinez-Barrondo, S., Florez, G., Sotomayor, E., Paredes, B., Alvarez, C., San Narciso, G., Carreño, E., Bombin, I., Alvarez, V., Coto, E., Fernandez, J.M., Bousoño, M., Bobes, J. Association study between obsessive-compulsive disorder and serotonergic candidate genes. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2008; 32: 765-770.
16. Kump, K.L., Kaye, W.H., Strober, M. The evolving genetic foundations of eating disorders. Psychiatric Clinics of North America. 2001; 24: 215-25.
17. Bulik, C.M., Sullivan, P.F., Tozzi, F., Furberg, H., Lichtenstein, P. Pedersen, N.L. Prevalence, heritability, and prospective risk factors for anorexia nervosa. Archives of General Psychiatry. 2006; 63:305-12.
18. Kendler, K.S., Gatz, M. Gardner, C.O., Pedersen, N.L. A Swedish national twin study of lifetime major depression. American Journal of Psychiatry. 2006; 163: 109-14.
19. van Grootheest, D.S., Boomsma, D.I., Hettema, J.M., Kendler, K.S. Heritability of obsessive-compulsive symptom dimensions. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2007 Dec. 14 [epub ahead of print].
20. Bosanac, P., Kurlender, S., Stojanovska, L., Hallam, K., Norman, T., McGrath, C., Burrows, G., Wesnes, K., Manktelow, T., Olver, J. Neuropsychological study of underweight and “weight-recovered” anorexia nervosa compared with bulimia nervosa and normal controls. International Journal of Eating Disorders. 2007; 40: 613-621.
21. Katzman, D.K., Christensen, B., Young, A.R., Zipursky, R.B. Starving the brain: structural abnormalities and cognitive impairment in adolescents with anorexia nervosa. Seminars in Clinical Neuropsychiatry. 2001; 6: 146-52.
22. Kerem, N.C., Katzman, D.K. Brain structure and function in adolescents with anorexia nervosa. Adolescent Medicine. 2003; 14: 109-18.
23. Chowdhury, U., Gordon, I., Lask, B., Watkins, B., Watt, H., Christie, D. Early-onset anorexia nervosa: is there evidence of limbic system imbalance? International Journal of Eating Disorders. 2003; 33: 388-96.
24. Miller, K.K., Deckersbach, T., Rauch, S.L., Fischman, A.J., Grieco, K.A., Herzog D.B., Klibanski A. Testosterone administration attenuates regional brain hypometabolism in women with anorexia nervosa. Psychiatry Research. 2004; 132: 197-207.
25. Sullivan, P.F. Mortality in anorexia nervosa. American Journal of Psychiatry. 1995; 152: 1073-4.
26. Keel, P.K., Dorer, D.J., Eddy, K.T., Franko, D., Charatan, D.L., Herzog, D.B. Predictors of mortality in eating disorders. Archives of General Psychiatry. 2003; 60: 179-83.
27. Commission on Adolescent Eating Disorders. Eating Disorders. In: Evans, D.E., Foa, E.B., Gur, R.E., Hendin, H., O’Brien, C.P., Seligman, M.E.P., Walsh, B.T. (Eds.) Treating and Preventing Adolescent Mental Health Disorders: What We Know and What We Don’t Know; A Research Agenda for Improving the Mental health of Our Youth. New York (NY). Oxford University Press; 2005. p. 258-81.
28. Kohn, M.R., Golden, N.H., Shenker, I.R. Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. Journal of Adolescent Health. 1998; 22: 239-43.
29. Shamim, T., Golden, N.H., Arden, M., Filiberto, L., Shenker, I.R. Resolution of vital sign instability; an objective measure of medical stability in anorexia nervosa. Journal of Adolescent Health. 2003; 32: 73-7.
30. Palla, B., and Litt, I.F. Medical complications of eating disorders in adolescents. Pediatrics. 1988; 81: 613-23.
31. Galetta, F., Franzoni, F., Cupisti, A., Belliti, D., Prattichizzo, F., Rolla, M. QT interval dispersion in young women with anorexia nervosa. Journal of Pediatrics. 2002; 140: 456-60.
32. Isner, J.M., Roberts, W.C., Heymsfield, S.B., Yager, J. Anorexia and sudden death. Annals of Internal Medicine. 1985; 102: 49-52.
33. Sharp, C.W., Freeman, C.P. The medical complications of anorexia nervosa. British Journal of Psychiatry. 1993; 162: 452-62.
34. Lantzouni, E., Frank, G.R., Golden, N.H., Shenker, R.I. 2002. Reversibility of growth stunting in early onset anorexia nervosa: a prospective study. Journal of Adolescent Health. 2002; 31: 162-5.
35. Bachrach, L.K., Guido, D., Katzman, D., Litt, I.F., Marcus, R. Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics. 1990; 86: 440-7.
36. Grinspoon, S. , Thomas, E., Pitts, S., Gross, E., Mickley, D., Miller, K., Herzog, D, Klibanski, A. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Annals of Internal Medicine. 2000; 133: 790-4.
37. Steinhausen, H.C., Grigoroiu-Serbanescu, M., Boyadjieva, S., Neumarker, K.J., Winkler Metzke, C. Course and predictors of rehospitalization in adolescent anorexia nervosa in a multisite study. International Journal of Eating Disorders. 2008; 41: 29-36.
38. Baran, S.A., Weltzin, T.E., Kaye, W.H. Low discharge weight and outcome in anorexia nervosa. American Journal of Psychiatry. 1995; 152: 1070-2.
39. Striegel-Moore, R.H., Leslie, D., Petrill, S.A., Garvin, V., Rosenheck, R.A. One-year use and cost of inpatient and outpatient services among female and male patients with an eating disorder: evidence from a national database of health insurance claims. International Journal of Eating Disorders. 2000; 27: 381-9.
40. Keel, P.K. Eating Disorders. Upper Saddle River, NJ: Prentice Hall; 2005.
41. Lock, J., Le Grange, D. Treatment Manual for Anorexia Nervosa: A Family-Based Approach. New York: Guilford Press; 2001.
This page was posted on May 15, 2008.
|
