Evaluation of unintentional weight loss - Differential diagnosis of symptoms (2023)

Unintentional weight loss is often defined as weight loss of at least 5% of the patient’s usual body weight that occurs within the preceding 6 to 12 months, and that is not the expected consequence of treatment of a known illness.[1]Wong CJ. Involuntary weight loss. Med Clin North Am. 2014;98:625-43.http://www.ncbi.nlm.nih.gov/pubmed/24758965?tool=bestpractice.com It is a diagnostic challenge because, while an underlying illness may be found after a thorough history and physical exam, the etiology may remain elusive and only be discovered through additional testing, the passage of time, or not at all. The most pressing concern is the assessment for the presence of cancer or other conditions for which early diagnosis may lead to better outcomes. There is a broad range of causes of unintentional weight loss including medical diseases, psychiatric illnesses, and social factors. These conditions may occur in isolation or in combination.


There is no formal consensus definition of unintentional weight loss; however, the weight loss must be considered unintentional by the patient and treating practitioner. The degree of weight loss has been defined in case series as being between 5% and 10% weight loss compared with usual body weight.[2]Marton KI, Sox HC, Krupp JR. Involuntary weight loss: diagnostic and prognostic significance. Ann Intern Med. 1981;95:568-74.http://www.ncbi.nlm.nih.gov/pubmed/7294545?tool=bestpractice.com[3]Rabinovitz M, Pitlik SD, Leifer M, et al. Unintentional weight loss: a retrospective analysis of 154 cases. Arch Intern Med. 1986;146:186-7.http://www.ncbi.nlm.nih.gov/pubmed/3942450?tool=bestpractice.com[4]Thompson MP, Morris LK. Unexplained weight loss in the ambulatory elderly. J Am Geriatr Soc. 1991;39:497-500.http://www.ncbi.nlm.nih.gov/pubmed/2022802?tool=bestpractice.com[5]Wallace JI, Schwartz RS, LaCroix AZ, et al. Involuntary weight loss in older outpatients: incidence and clinical significance. J Am Geriatr Soc. 1995;43:329-37.http://www.ncbi.nlm.nih.gov/pubmed/7706619?tool=bestpractice.com[6]Bilbao-Garay J, Barba R, Losa-Garcia JE, et al. Assessing clinical probability of organic disease in patients with involuntary weight loss: a simple score. Eur J Intern Med. 2002;13:240-5.http://www.ncbi.nlm.nih.gov/pubmed/12067819?tool=bestpractice.com[7]Chen SP, Peng LN, Lin MH, et al. Evaluating probability of cancer among older people with unexplained, unintentional weight loss. Arch Gerontol Geriatr. 2010;50(suppl 1):S27-9.http://www.ncbi.nlm.nih.gov/pubmed/20171452?tool=bestpractice.com[8]Wu JM, Lin MH, Peng LN, et al. Evaluating diagnostic strategy of older patients with unexplained unintentional body weight loss: a hospital-based study. Arch Gerontol Geriatr. 2011;53:51-4.http://www.ncbi.nlm.nih.gov/pubmed/21071102?tool=bestpractice.com[9]Bosch X, Monclús E, Escoda O, et al. Unintentional weight loss: Clinical characteristics and outcomes in a prospective cohort of 2677 patients. PLoS One. 2017 Apr 7;12(4):e0175125.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175125http://www.ncbi.nlm.nih.gov/pubmed/28388637?tool=bestpractice.comSimilarly, there is no strict definition of the time period in which the unintentional weight loss should occur; however, most case series used the criteria of weight loss developing within the preceding 3 to 12 months.

Related syndromes include cachexia and sarcopenia. Cachexia is a syndrome of weight loss characterized by decreased muscle mass in the presence of the metabolic effects of an underlying illness such as some types of cancer or advanced heart failure.[10]Evans WJ, Morley JE, Argiles J, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793-9.http://www.ncbi.nlm.nih.gov/pubmed/18718696?tool=bestpractice.com While all patients with cachexia have unintentional weight loss, not all patients with unintentional weight loss have cachexia. Sarcopenia is a geriatric syndrome of diminished muscle mass and function, which may or may not be accompanied by unintentional weight loss.

A consensus definition of malnutrition includes unintentional weight loss (>5% in 3 months, or >10% of indefinite time) as a component of one set of diagnostic criteria.[11]Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for malnutrition: an ESPEN consensus statement. Clin Nutr. 2015;34:335-40.http://www.clinicalnutritionjournal.com/article/S0261-5614%2815%2900075-8/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/25799486?tool=bestpractice.com

In the United States, the Centers for Medicare and Medicaid Services require that long-term care facilities conduct an assessment when a resident has an unplanned weight loss problem (5% change in 30 days or 10% change in 180 days).[12]Centers for Medicare and Medicaid Services, State Operations Manual, Appendix PP – Guidance to Surveyors for Long Term Care Facilities. Aug 2007 [internet publication].https://www.cms.gov/Regulations-and-Guidance/Legislation/CFCsAndCoPs/Downloads/som107ap_pp_guidelines_ltcfpdf


In population-based cohort studies, the prevalence of unintentional weight loss varies between 7% and 13%, with differences attributable to both demographics and duration of follow-up.[13]Gregg EW, Gerzoff RB, Thompson TJ, et al. Intentional weight loss and death in overweight and obese U.S. adults 35 years of age and older. Ann Intern Med. 2003;138:383-9.http://annals.org/article.aspx?articleid=716098http://www.ncbi.nlm.nih.gov/pubmed/12614090?tool=bestpractice.com[14]Wannamethee SG, Shaper AG, Lennon L. Reasons for intentional weight loss, unintentional weight loss, and mortality in older men. Arch Intern Med. 2005;165:1035-40.http://archinte.jamanetwork.com/article.aspx?articleid=1152796http://www.ncbi.nlm.nih.gov/pubmed/15883243?tool=bestpractice.com[15]Sahyoun NR, Serdula MK, Galuska DA. The epidemiology of recent involuntary weight loss in the United States population. J Nutr Health Aging. 2004;8:510-7.http://www.ncbi.nlm.nih.gov/pubmed/15543425?tool=bestpractice.com The prevalence in older adults (those ages over 65 years) is reportedly 15% to 20%, however clinical and epidemiologic studies have reported even higher prevalence in certain populations, with as many as 27% of community dwelling elderly people and 50% to 60% of nursing home residents being affected.[16]Alibhai SM, Greenwood C, Payette H. An approach to the management of unintentional weight loss in elderly people. CMAJ. 2005 Mar 15;172(6):773-80.https://www.doi.org/10.1503/cmaj.1031527http://www.ncbi.nlm.nih.gov/pubmed/15767612?tool=bestpractice.com[17]Bouras EP, Lange SM, Scolapio JS. Rational approach to patients with unintentional weight loss. Mayo Clin Proc. 2001 Sep;76(9):923-9.https://www.doi.org/10.4065/76.9.923http://www.ncbi.nlm.nih.gov/pubmed/11560304?tool=bestpractice.com For patients with the most clinically applicable presentation (i.e., weight loss occurring within the preceding 6 months), the prevalence is approximately 7%.[15]Sahyoun NR, Serdula MK, Galuska DA. The epidemiology of recent involuntary weight loss in the United States population. J Nutr Health Aging. 2004;8:510-7.http://www.ncbi.nlm.nih.gov/pubmed/15543425?tool=bestpractice.com

An association with mortality and unintentional weight loss has been demonstrated in a systematic review and meta-analysis of observational studies; subgroup analyses found that unintentional weight loss was significantly associated with increased mortality risk in older people and in overweight and obese subjects.[18]De Stefani FDC, Pietraroia PS, Fernandes-Silva MM, et al. Observational evidence for unintentional weight loss in all-cause mortality and major cardiovascular events: a systematic review and meta-analysis. Sci Rep. 2018 Oct 18;8(1):15447.https://www.doi.org/10.1038/s41598-018-33563-zhttp://www.ncbi.nlm.nih.gov/pubmed/30337578?tool=bestpractice.comIn patients with recent unintentional weight loss (i.e., within 6 months), weight loss of 5% or greater was associated with an increase in subsequent mortality.[15]Sahyoun NR, Serdula MK, Galuska DA. The epidemiology of recent involuntary weight loss in the United States population. J Nutr Health Aging. 2004;8:510-7.http://www.ncbi.nlm.nih.gov/pubmed/15543425?tool=bestpractice.com

Unintentional weight loss has been associated with increased perioperative complications in patients undergoing gynecologic surgery, colorectal surgery, and surgery for disseminated cancer.[19]Pache B, Grass F, Hübner M, et al. Prevalence and consequences of preoperative weight loss in gynecologic surgery. Nutrients. 2019 May 17;11(5):1094.https://www.doi.org/10.3390/nu11051094http://www.ncbi.nlm.nih.gov/pubmed/31108841?tool=bestpractice.com[20]Moghadamyeghaneh Z, Hanna MH1, Hwang G, et al. Outcome of preoperative weight loss in colorectal surgery. Am J Surg. 2015;210:291-7.http://www.ncbi.nlm.nih.gov/pubmed/25990792?tool=bestpractice.com[21]Thirunavukarasu P, Sanghera S, Singla S, et al. Pre-operative unintentional weight loss as a risk factor for surgical outcomes after elective surgery in patients with disseminated cancer. Int J Surg. 2015;18:7-13.http://www.ncbi.nlm.nih.gov/pubmed/25865083?tool=bestpractice.com

Unintentional weight loss represents a striking contrast to the epidemics of obesity in many countries and the commonplace experience of unsuccessful attempts at intentional weight reduction. Furthermore, unintentional weight loss may be under recognized in the primary care setting.[22]El-Kareh R, Pazo V, Wright A, et al. Losing weights: failure to recognize and act on weight loss documented in an electronic health record. J Innov Health Inform. 2015;22:316-22.http://hijournal.bcs.org/index.php/jhi/article/view/137/840http://www.ncbi.nlm.nih.gov/pubmed/26577421?tool=bestpractice.com


The pathophysiology varies depending on the etiology. Weight homeostasis is a complex process that includes the availability of food, physical activity, possible environmental exposures, and hormonal control with peptides such as leptin, cholecystokinin, and ghrelin.[23]Guyenet SJ, Schwartz MW. Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab. 2012;97:745-55.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319208http://www.ncbi.nlm.nih.gov/pubmed/22238401?tool=bestpractice.com

Unintentional weight loss owing to cachexia is associated with cytokines (e.g., tumor necrosis factor-alpha) that suppress appetite, promote muscle and fat breakdown, and increase energy expenditure.[24]Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metabolism. 2012;16:153-66.http://www.ncbi.nlm.nih.gov/pubmed/22795476?tool=bestpractice.com[25]Argiles JM, Busquets S, Felipe A, et al. Molecular mechanisms involved in muscle wasting in cancer and ageing: cachexia versus sarcopenia. Int J Biochem Cell Biol. 2005;37:1084-104.http://www.ncbi.nlm.nih.gov/pubmed/15743680?tool=bestpractice.com Normal homeostasis signaling is disrupted in cachexia syndromes, while these mechanisms are preserved in the setting of weight loss due purely to inadequate caloric intake.

Differential diagnosis

The differential diagnosis is extremely broad. In case series, the most common etiologies are:[26]McMinn J, Steel C, Bowman A. Investigation and management of unintentional weight loss in older adults. BMJ. 2011 Mar 29;342:d1732.http://www.ncbi.nlm.nih.gov/pubmed/21447571?tool=bestpractice.com

  • Malignancy

  • Gastrointestinal conditions

  • Psychiatric causes.

Other etiologies that should be considered include:

  • Cachexia syndromes associated with organ failure (e.g., heart failure, chronic obstructive pulmonary disease, renal failure)

  • Endocrinopathies (e.g., hyperthyroidism, diabetes mellitus, adrenal insufficiency)

  • Serious infections (e.g., tuberculosis and HIV)

  • Medication side effects

  • Substance misuse

  • Social factors that prevent adequate access to food.

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