Failure to Thrive in Old

Home , Anorexia (symptom), Cachexia

MINI-REVIEW Failure To Thrive in Old Age: Follow-up on a Workshop Downloaded from https://academic.oup.com/biomedgerontology/article/52A/6/M333/571756 by guest on 28 September 2021 Roy B. Verdery

Arizona Center on Aging, Tucson.

HE failure to thrive syndrome (FIT) was noted by an clude sarcopenia, loss of physical functioning, decline in T Institute of Medicine report of 1991 to be one area in the ability to accomplish self-care ADLs, presence of labo- geriatrics needing further research (1). The National Insti- ratory abnormalities consistent with dehydration (e.g., ele- tute on Aging and the Arizona Center on Aging conducted vated BUN/creatinine) (7), and other laboratory abnormali- a workshop on FIT in September, 1993. Participants with ties associated with poor prognosis of elderly people expertise in geriatrics, gerontology, medicine, physiology, including hypoalbuminemia (8) and hypocholesterolemia and psychology (see Acknowledgments) met for three days (9). More than 50% of people older than 65, hospitalized to discuss six general areas: (a) natural history and epide- with pre-existing weight loss, continue to lose weight after miology of FIT; (b) clinical problems associated with FIT; hospitalization, and over 75% of these people with irre- (c) role of nutrition in the etiology of FIT; (d) role of cy- versible weight loss die within 1 year (10). tokines and immunodeficiency in the etiology of FIT; (e) endocrine and metabolic factors in FIT; and (f) interven- Clinical Problems Associated with FTT tions to prevent or reverse FIT. Since 1993, much of the Clinical problems associated with FIT include hip frac- work presented at the conference has been published by in- ture (11-13), pneumonia (14), decubitus ulcers (15,16), de- dividual participants. This report is a follow-up, describing pression (17), declining physical functioning (18), sarcope- current ideas about FIT. nia (19), and frailty (20). The major etiological issues in FIT is a syndrome (not a diagnosis) related to classical FTT following hip fracture are the relative roles of immo- nutritional abnormalities including nutritional marasmus bility, confusion, infection, and development of pressure and hypoalbuminemic, inflammation-associated malnutri- sores (21,22). Both hip fracture and pneumonia can be tion. This relationship sets the stage for the principal prob- viewed either as causes of FTT or hallmarks of pre-existing lem in understanding and managing FIT: determination if FTT. From 30 to 60% of older people hospitalized with hip FIT is (a) due to starvation; (b) due to undiagnosed disease fracture pneumonia lose physical functioning and die which needs to be identified and treated, or (c) due to some within one to two years. unknown process uniquely associated with aging. As proposed by the late Dr. Daniel Rudman, FIT can be subclassi- Nutritional Problems Associated with FTT fied into nonorganic and organic FIT as shown in Figure 1. Anorexia of aging is seen in both people and animals In addition to malnutrition, FTT is associated with im- (23,24). The mechanisms involved are not well understood, mune activation, the physiologic stress response, involu- although the hypothalamus and various neuropeptides are tional changes in anabolic hormones, and the (semantically undoubtedly involved (25,26). Semi-starvation seen in FTT paradoxical) chronic-acute phase response. and acute illness leads to two characteristic kinds of defi- ciency: (a) nutritional marasmus with decreased body fat Epidemiology and Natural History of FTT stores (75% fat loss and 25% lean tissue loss) due to semi- Unexplained weight loss is a definition of FIT suitable starvation (27,28), and (b) general catabolic responses for epidemiological studies of the syndrome (2,3). FIT oc- (75% lean tissue loss [including bone loss] and 25% fat currences in hospitals, outpatient clinics, and the commu- loss) to injury, inflammation, and infection seen in specific nity have been separately considered: estimates of the processes including severe head injury, multiple trauma, prevalence of FIT range from 5-35% in people living in and burns (29). Poor food intake due to anorexia and dys- the community (4), 25-40% among nursing home residents geusia is potentially reversible (30). (5), and 50-60% in hospitalized veterans (6). Prevalence FTT may be due in part to age-associated "energy dys- increases with age from 55 to 80 years old, the average age regulation" (31,32). Following a period of underfeeding, of hospitalized veterans where 50-60% had FIT (6). Epi- younger people are hyperphagic and rapidly gain back any demiologically important concomitants of weight loss in- lost weight, but older people do not have the compensatory

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Alzheimer's disease this process may be relevant to the Non-organic causes pathology of the loss of neurons (56,57). Hypercatabolism and hypoanabolism in patients with Depression FTT is affected by growth hormone and IGFl physiology, FTT Adverse psychosocial factors modulated by IGF binding proteins (58,59). IGFl levels Poor quality care correlate with changes in lean body mass, and the decline in IGFl levels that occurs with aging correlates with the de- Organic causes crease in lean body mass (59,60). Following burns, growth hormone administration increases net anabolism, although

GH also increases catabolism (61). Simultaneous adminis- Downloaded from https://academic.oup.com/biomedgerontology/article/52A/6/M333/571756 by guest on 28 September 2021 Conventional diseases Novel mechanisms (e.g. cancer, heart failure, (e.g. immunosenescence, energy tration of IGFl and GH is synergistic and results in positive TB, hypothyroidism) dysregulation, neuroendocrine protein balance even in severe caloric restriction (62). GH, imbalance) even with IGFl, may not reverse FTT in people who have lost most of their fat mass (63). Figure 1. Schematic proposed by Dr. Daniel Rudman for the Workshop on Failure To Thrive in Old Age, illustrating division of FTT into nonor- Interventions To Prevent or Reverse FTT ganic and organic causes, and organic causes into known and hypothetical age-associated etiologies. Food supplementation is the most important potential in- tervention in FTT (64), because studies of selected individ- uals have shown that it is possible to cause increases in weight, albumin, erythroid and myeloid cell mass, and de- hyperphagia and do not regain that weight (33). Similarly, crease anergy by nutritional supplementation (65). Alterna- following a period of overfeeding, older men do not have tively, medications or flavor enhancers that increase food the compensatory decrease in food intake seen in younger intake, or eliminating medications that cause anorexia, ac- men (34,35). Similar dysregulation of water intake occurs (36-38). And, in addition to energy and fluid balance, complish the same thing (30). An important paradox in changes in protein balance and turnover occur with age these efforts to increase food intake by nutritional supple- (39,40). Because of dysregulation, acute weight loss due to mentation or appetite stimulation is seen in the study of di- illness may be irreversible (41). etary restricted animals (66,67), where dramatic improve- ments in most risk factors for chronic disease and early death were improved (68). In addition to food, exercise Role ofCytokines in Immunodeficiency in FTT helps reverse functional deficits seen in FTT (69,70). Abuse Clinical abnormalities accompanying FTT are similar to and neglect are reversible social etiologies of FTT, and in those accompanying the acute phase response, character- some nursing homes, high frequencies of FTT may be re- ized by fever, anorexia, changes in synthesis of many lated to poor quality of care (71). plasma proteins, decreased erythropoiesis, leukocytosis, Pharmacologic agents other than GH or IGFl, which thrombocytosis, decreased bone density, increased protein have been considered for treating FTT, include antiinflam- metabolism in muscle, and many endocrine changes that matory agents, agents that might stimulate appetite, cannabi- might be referred to as the stress response. Regulation of noids, cyproheptadine, and megestrol acetate (72,73), or both the acute and chronic-acute phase response is effected hydrazine sulfate, which inhibits gluconeogenesis and may by several cytokines (42,43); and one cytokine in particular, decrease protein breakdown (74). None of these drugs, interleukin 6 (IL-6) might be the most important in age-as- however, has been shown to be effective in treating FTT sociated immune-dysregulation and disease (44-46). In ad- in aging. dition, IL-1 and TNF have similar effects, and both trans- forming factor beta and gamma interferon also influence the acute phase response (47). Chronic conditions including Conclusion rheumatoid arthritis, end-stage heart disease, and AIDS ap- In the 4 years following the Workshop on Failure To pear to cause FTT, at least in part because of chronic or re- Thrive in Old Age, more than 100 articles on epidemiologi- peated elevations of inflammatory cytokines (48-50). Dys- cal, medical, physiological, psychological, and biochemical regulation of IL-6 production is related to the development aspects of the failure to thrive syndrome have been pub- of age-associated lymphoma (51), and dysregulation of cy- lished. Although we now know more about these involutional tokine production may lead to weight loss, sarcopenia, os- processes that occur in aging people, there is little new in- teoporosis, decreased food intake, hypoalbuminemia, and sight into what can be done to reverse these end-of-life pro- hypocholesterolemia (52-54). cesses. Thus, the stage is set for testing new interventions.

Endocrine and Metabolic Factors in FTT ACKNOWLEDGMENTS Endocrine and other metabolic factors regulate the This work was supported in part by the National Institute on Aging, (SERCA, K01 AG00414), and the Arizona Center on Aging, University of changes in body composition, synthesis of hepatic proteins, Arizona. and changes in food intake and energy expenditure seen in Organizers of the 1992 Workshop were E.C. Hadley, D.A. Lipschitz, D. FTT. In acute illness, there is direct cytokine inhibition of Rudman, and R.B. Verdery. Participants and discussants included TSH production (55). Hypermetabolism (increased energy R.M. Allman, B.R. Bistrian, J.P. Blass, J. Boyer, P. Brannon, J. Busby- expenditure), occurs at the same time as the anorexia. In Whitehead, J.G. Cannon, G. Cizza, D.R. Clemmons, PL. Colvin, W.B. MINI-REVIEW M335

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THE JOHNS HOPKINS UNIVERSITY TENURE TRACK ACADEMIC FACULTY POSITION: GERIATRICIAN / CLINICAL RESEARCH CENTER ON AGING AND HEALTH / DEPARTMENT OF MEDICINE The Johns Hopkins University School of Medicine is conducting a search for a Geriatrician with expertise in clinical research for a tenured track faculty position in a new, multidisciplinary Center on Aging and Health. This individual will join an ongoing research program focused on prevention of disease, disaiblity, and frailty in aging. The individual will collaborate on ongoing research and will be expected to develop independent investigation. This position will be based in a multidisciplinary Center for research and education on aging, with opportunities for geriatric clinical practice in the Division of Geriatrics. The position will include active collaboration with investigators throughout the Schools of Medicine and Hygiene and Public Health. The ideal candidate would be an associate or assistant professor with formal training in epidemiology and/or clinical investigation. Academic rank and salary will be commensurate with the candidate's experience. Eligible candidates should submit a letter of interest and a curriculum vitae, and a list of at least three references to: Linda P. Fried, M.D., M.P.H. Director, Center on Aging and Health The Johns Hopkins Medical Institutions 2024 East Monument Street, Suite 2-600 Baltimore, MD 21205 Phone:(410)955-0491 The Johns Hopkins University School of Medicine is an Equal Opportunity/Affirmative Action employer.