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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Javaria Anwer M.D. Cafer Zorkun, M.D., Ph.D. ; M.Umer Tariq ;
Synonyms and keywords: weight reduction, elderly, malignancy, infection, dietary supplements, nutrition.
Weight loss, in the context of medicine or health or physical fitness, is a reduction of the total body weight. An individual may lose weight due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue. Weight loss is a product of negative energy balance and can be unintentional or intentional. It can be a side effect of therapeutic drugs. The most common cause among the elderly is cancer. A thorough history with nutritional assessment, calorie count, patient's living conditions, neurocognitive dysfunction, appropriate labs and imaging findings are necessary. Until a diagnosis is made, nutritional supplementation should not be delayed in the interest of a patient's health. Treating the underlying cause, regular follow-up, and patient counseling are important components of weight loss management.
- Weight loss is a product of negative energy balance. When the human body spends more energy in work and heat than it is gaining from food or other dietary supplements, it will catabolize stored reserves of fat or muscle.
- There is no formal classification system for weight loss. Based on the cause, we attempt to provide a general outline of the types of weight loss.
|Causes of weight loss|
|Intentional weight loss||Unintentional weight loss|
❑ Exercise and dietary modifications
❑ Bariatric surgery such as laproscopic sleeve gastrectomy, Roux-en-Y gastric bypass, and adjustable gastric banding
|Malnutrition such as protein energy malnutrition||Altered metabolism||Malabsorption or excretory dysfunction|
❑ Nausea and vomiting
❑ Endocrine disorders
❑ Autoimmune disorders
❑ Chronic diarrhea
Unintentional Weight Loss
- A myriad of additional scientific considerations are applicable to weight loss, including but not limited to physiological and exercise sciences, nutrition science, behavioral sciences, and other sciences.
- One area involves the science of bioenergetics including biochemical and physiological energy production and utilization systems, that is frequently evidence of diabetes, and ketone bodies, acetone particles occurring in body fluids and tissues involved in acidosis, also known as ketosis, somewhat common in severe diabetes.
- Substantial, unintentional weight loss can be a symptom of an acute or chronic illness, especially if other evidence is demonstrated.
- Weight loss accompanied by insatiable thirst, hunger and fatigue may indicate diabetes mellitus (DM). To read more about diabetes mellitus, click here. Diabetes characterized by an abnormal accumulation of carbohydrates in the bloodstream due to insufficient production of or tissue resistance to insulin. Poor management of insulin-dependent diabetes mellitus (IDDM), also known as diabetes mellitus type I, leads to an excessive amount of glucose and an insufficient amount of insulin in the bloodstream. It triggers the release of triglycerides from adipose tissues and catabolism of amino acids in the muscle tissue. This results in a loss of both fat and lean mass, predisposing a significant reduction in total body weight.
- Infections such as HIV may alter the metabolism, leading to weight loss. *
- Hormonal disruptions, such as an overactive thyroid (hyperthyroidism), may also lead to weight loss.
- In addition to weight loss due to a reduction in fat and lean mass, illnesses such as diabetes, certain medications, lack of fluid intake, and other factors can trigger fluid loss. A fluid loss in addition to a reduction in fat and lean mass poses a risk for cachexia. Loss of muscle mass in cachexia is due to combined effect of decreased protein synthesis in combination with an increased protein degradation via lysosomes and ubiquitin-proteasome pathway.
Intentional Weight Loss
- Intentional weight loss may refer to the loss of total body mass in an effort to improve fitness, health, or appearance.
- It is not uncommon for people who are already at a medically healthy weight to intentionally lose weight. In some cases, it is intending to improve athletic performance or to meet weight classifications in a sport.
- In other cases, the goal is to attain a more attractively shaped body. On the other hand, being underweight is associated with health risks.
- Health problems can include susceptibility to infections, osteoporosis, decreased muscle strength, trouble regulating body temperature, and even increased risk of death.
Therapeutic Weight Loss Techniques
- Overweight and obese individuals face a greater risk of health conditions such as type 2 diabetes, heart disease, high blood pressure, stroke, osteoarthritis, and certain types of cancers.
- Therapeutic weight loss, in individuals who are overweight, can decrease the likelihood of developing diseases such as diabetes.
- For healthy weight loss, a physician should be consulted to develop a weight loss plan that is tailored to the individual. The least intrusive weight loss methods and those most often recommended by physicians are lifestyle modifications. Usually, health professionals will recommend that their overweight patients combine a reduction of the caloric content of the diet with an increase in physical activity.
- Other methods of losing weight include use of drugs and supplements that decrease appetite, block fat absorption, or reduce stomach volume. Surgery is another method. Bariatric surgery artificially reduces the size of the stomach, limiting the intake of food energy. Some of these treatments may have serious side-effects.
- Unintentional weight loss:
- Nicotine and smoking (may be an intentional caue).
- Drug side effects (mentioned below)
- Age >65 years:
- Malignancies (specifically digestive and non-hematologic)
- Neurological disorders: Dementia, stroke, parkinson's disease
- Oral disorders
- Chronic disorders: Chronic renal failure
- Age <65 years:
- Endocrine disorders (such as hyperthyroidism)
- Infections such as TB and HIV
- Psychiatric disorders such as depression, anxiety, and OCD, eating disorders
- Malignancies such as hematologic
- Intentional weight loss: Dieting, dexatrim, and aerobic exercise.
Causes by Organ System
Causes in Alphabetical Order
- Abatacept Injection (patient information)
- Acute lymphoblastic leukemia
- Acute myeloid leukemia
- Acute promyelocytic leukemia
- Addison's disease
- Adjustable gastric band
- Adrenocorticotropic hormone deficiency
- Aerobic exercise
- Aggressive NK-cell leukemia
- Alcoholic Hepatitis
- Allopurinol (patient information)
- Amiodarone Oral (patient information)
- Amphotericin B Injection (patient information)
- Anorexia nervosa
- Arsenic Poisoning
- Aspergillus clavatus
- Aspergillus fumigatus
- Autoimmune pancreatitis
- Barrett's esophagus
- Basedow syndrome
- Benzodiazepine withdrawal syndrome
- Bevacizumab Injection (patient information)
- Blind loop syndrome
- Botulinum toxin
- Bulimia nervosa
- Bumetanide (patient information)
- Busulfan (patient information)
- Calcitriol (patient information)
- Calorie restriction
- Cannabis (drug)
- Carboplatin (patient information)
- Carmustine (patient information)
- Castleman's disease
- Celiac disease
- Cervical cancer
- Cetuximab Injection (patient information)
- Chagas disease
- Chlorambucil (patient information)
- Chronic fatigue syndrome
- Chronic Obstructive Pulmonary Disease
- Chronic pancreatitis
- Chronic Renal Failure
- Chronic wasting disease
- Churg-Strauss Syndrome
- Clofarabine Injection (patient information)
- Cogan syndrome
- Colorectal cancer
- Congestive Heart Failure
- Crohn's disease
- Cystic Fibrosis
- Cytarabine (patient information)
- Diabetes mellitus type 1
- Dientamoeba fragilis
- Diphyllobothrium infection
- Donepezil (patient information)
- Eating disorder
- ECA stack
- Empyema Thoracis
- Enfuvirtide Injection (patient information)
- Entamoeba histolytica
- Eosinophilic gastroenteritis
- Esophageal cancer
- Esophageal candidiasis
- Familial adenomatous polyposis
- Fasciola hepatica
- Felbamate (patient information)
- Fluorouracil (patient information)
- Fluticasone Nasal Spray (patient information)
- Fluticasone Oral Inhalation (patient information)
- Folate deficiency
- Food intolerance
- Frailty syndrome
- Fucus vesiculosus L.
- Fundic gland polyposis
- Furosemide (patient information)
- Galantamine (patient information)
- Gallbladder cancer
- Gastric bypass surgery
- Gastric lymphoma
- Gastroesophageal reflux disease
- Gatifloxacin (patient information)
- Gefitinib (patient information)
- Giardia lamblia
- Glucagonoma Syndrome
- Glucose-galactose malabsorption
- Graves' Disease
- Hashimoto's thyroiditis
- Hepatitis C
- Hodgkin's lymphoma
- Hydrolyzed collagen (hydrolysate)
- Hydroxycitric acid
- Hyperemesis gravidarum
- Indapamide (patient information)
- Inflammatory bowel disease
- Interferon beta-1a Intramuscular Injection (patient information)
- Interferon beta-1a Subcutaneous Injection (patient information)
- Interferon Beta-1b Injection (patient information)
- Interstitial nephritis
- Irritable bowel syndrome
- Ischemic colitis
- Kaposi's sarcoma
- Kikuchi disease
- Krabbe disease
- Leflunomide (patient information)
- Leishmania infection
- Leuprolide (patient information)
- Liothyronine (patient information)
- Lithium (patient information)
- Liver Failure
- Lomustine (patient information)
- Lung cancer
- Mantle cell lymphoma
- Marburg virus
- Mechlorethamine (patient information)
- Mediastinal tumor
- Melphalan (patient information)
- Ménétrier's disease
- Mercaptopurine (patient information)
- Methsuximide Oral (patient information)
- Micropolyspora faeni
- Mini sleeve gastrectomy
- Mitochondrial myopathy
- Mucor stolonifer
- Multiple endocrine neoplasia type 1
- Mycobacterium avium complex infection
- Natalizumab injection (patient information)
- Neuroendocrine tumors
- Nevirapine (patient information)
- Non-Hodgkin lymphoma
- Oxaliplatin injection (patient information)
- Pancreatic cancer
- Parkinson's disease
- Peginterferon alfa-2a (patient information)
- Peginterferon alfa-2b (patient information)
- Pemetrexed injection (patient information)
- Pemoline (patient information)
- Peptic ulcer
- Phenytoin oral (patient information)
- Piroxicam (patient information)
- Polyarteritis nodosa
- Polymyalgia Rheumatica
- Posaconazole (patient information)
- Pott's disease
- Pramipexole (patient information)
- Protriptyline (patient information)
- Pulmonary alveolar proteinosis
- Pyloric stenosis
- Q Fever
- Rasagiline (patient information)
- Renal cell carcinoma
- Ribavirin (patient information)
- Rift Valley fever
- Rivastigmine (patient information)
- Selective serotonin reuptake inhibitor
- Short bowel syndrome
- Sitophilus granarius
- Small intestine cancer
- Spironolactone and hydrochlorothiazide (patient information)
- SSRI discontinuation syndrome
- Stomach cancer
- Sunitinib (patient information)
- Systemic lupus erythematosus
- Takayasu's Arteritis
- Tamoxifen (patient information)
- Thioguanine (patient information)
- Thiotepa (patient information)
- Thyroglobulin (patient information)
- Torsemide Injection (patient information)
- Toxic multinodular goiter
- Trimetrexate Glucuronate (patient information)
- Ulcerative colitis
- Vorinostat (patient information)
- Waldenström's macroglobulinemia
- Whipple disease
- Zoledronic Acid Injection (patient information)
- Zonisamide (patient information)
- A thorough history includes past medical history to assess for any underlying diseases. For the elderly assess the living conditions, for neglect, neurocognitive deficits, dementia,stroke, and other disorders that may hamper access to food. Food, nutrition, access, swallowing, gut motility, absorption, excretion, all functions should be accessed. It is important to assess the amount of weight in the past three months and the pattern of weight loss. It may be assessed by changing the size of the clothes.
Weight loss grading system (WLGS)
- A grading system utilizes the % weight loss and BMI to grade the weight loss between 0-4. The disease prognosis and patient survival changes with the grade change usually moving from good prognosis to worse with low survival rates.
- Among patients with incurable cancer, WLGS 4 was found to be independently associated with an increased symptom burden and worse prognosis. The quality of life also becomes poor with increasing grades of WLGS.
- Children: A complete nutritional assessment includes:
- Medical history (includes birth history, developmental history).
- Nutritional history such as dietary intake.
- Physical examination that includes Anthropometric history, pubertal staging, bone age, and labs to assess the nutritional status.
- Linear growth assessment, bone densitometry, resting energy expenditure via indirect calorimetry, growth charts are some of the other methods utilized under specific circumstances.
- Adults: A thorough history of food availability, financial status, neurocognitive disability, abuse, weight changes in the past three months should be considered.
- Elderly: Mini-nutritional assessment is a vital component of geriatric evaluation. It includes:
- Anthropometric assessment: BMI, weight loss during the past three months.
- General assessment such as living conditions, mobility, neuropsychological issues, skin [ulcers]], prescription drug use.
- Dietary assessment: Meals, servings, protein intake, water intake, and mode of feeding.
- Self-assessment: If the patient considers themselves having nutritional problems.
There are multiple variables and modifications of the nutritional assessment form.
- Caloric intake record is of special importance among critically ill patients in ICU and calorie-protein intake should be within certain limits.
- A complete physical exam includes: Vital signs, HEENT, visual acuity, cardiovascular exam, GI exam (includes oral, abdominal, rectal exam), respiratory exam, and neurological examination.
- To read more about a complete physical exam click here.
The following laboratory studies should be considered:
- CBC with differential : Include peripheral smear if anemia or other hematological pathologies suggesting RBC pathology. Infection (high WBC count), and parasite infection (eosinophilia).
- ESR, CRP, LDH: If infection is suspected.
- Glucose and/or HbA1c: To assess/ diagnose if diabetes is suspected.
- CMP: Assess organ function, metabolism, and electrolyte imbalances.
- Lipid profile: Assesses nutritional status.
- TSH, free T4: To assess the thyroid functional status.
- Urinalysis: Assess for UTIs, albuminuria, hemoglobinuria, diabetes, etc.
- FOBT: Lower GI bleed such as in colon cancer, platelet disorders.
- PTH levels
- HIV test: As the disease is associated with infections, malignancies and itself weight loss.
Electrolyte and Biomarker Studies
- Morning ACTH stimulation test should be done if there is a suspicion of adrenal insufficiency.
- To read more about the diagnostic test for Addison's disease please click here.
- QRS voltage may increase with dramatic weight loss.
- An x-ray may be helpful in the diagnosis of the primary focus of infection or malignancy. Findings on an x-ray suggestive of the lung cancer include solitary or diffuse mass. Comparing a solitary mass with the previous Xray or ordering a CT scan is usually the next step in evaluating a solitary lung mass.
- Chest X-ray is usually the initial test that serves the purpose of screening for a focus.
Echocardiography and Ultrasound
- Ultrasound: May be helpful in the diagnosis of cysts and malignancy. Findings on ultrasound suggestive of malignancy include blood supply
- Echocardiography: Heart failure assessment and tumors.
- Whole body CT scan has the diagnostic yield of 33.5% for patients with unexplained weight loss. A lung CT demonstrating a cancer may have central or peripheral mass with variable borders. The characteristic help evaluate and assess the malignant potential of the mass.
- CT may also be used to assess the possible metastasis of a disease with a small primary focus.
Other Diagnostic Studies
- Endoscopy or [colonoscopy]] may be helpful in the diagnosis/ screening for the diseases that cause weight loss.
- Age-appropriate screenings for cancers include:
- Upper GI endoscopy to assess for stomach cancer, peptic ulcer.
- Colonoscopy for colon cancer
Treating the underlying disease and nutritional support and/ or appetite stimulants to prevent further weight loss.
- Oropharyngeal or esophageal dysphagia:
- Pureed or thickened liquids.
- Speech therapy for oropharyngeal issues.
- Nutritional deficiency:
- Decreased dietary restrictions, increased oral intake.
- Dietary supplements in addition to regular meals.
- Nutritionist referral.
- Neglect: Social Services referral
- Electrolyte imbalances:
- Severe: IV fluids to replenish electrolytes is severe cases. Specific treatments such as, hypokalemia medical therapy, hypomagnesemia medical therapy, hyponatremia medical therapy, hyperkalemia medical therapy, and hypernatremia medical therapy.
- Moderate/ mild: Adequate fluid intake and dietary supplements and tablets.
- Adjuvant or non-adjuvant radiotherapy/ chemotherapy.
- Anorexia associated with malignancy and AIDS: Appetite stimulants such as megestrol 320 mg/day for adults and lower dosages for elderly. Dronabinol oral solution has quicker onset of action than the capsule form.
- Chemotherapy induced nausea and vomiting: Anti-emetics such as ondansetron and metoclopramide.
- Malabsorption syndromes:
- Ulcerative colitis medical therapy, Crohn's disease medical therapy.
- Pancreatic enzymes for malabsorption in the pancreas.
- Refer for specialist care such as a psychotherapist and/or a psychiatrist.
- Mirtazapine helps stimulate hunger especially among patients of anorexia nervosa with depression.
Cost-Effectiveness of Bariatric Surgery
- A cohort study from United Kingdom described bariatric surgery as not cost-saving but cost-effective. It describes that to obese individuals, the increment in health care costs are exceeded by health benefits.
- In a United States study utilizing microsimulation model, laparoscopic sleeve gastrectomy was described a most cost-effective for individuals with BMI between 35-39.9 kg/m2.
- Patient and caregiver education and counseling.
- Aggressive therapy with a psychiatrist or psychologist for anorexia nervosa.
- Anti-emetics such as aprepitant to prevent chemotherapy-induced nausea and vomiting.
- A 4%–5% or more of body weight loss within a year, or 10% or > over 5–10 years or longer, is associated with an increased mortality or morbidity/ both.
- ↑ Gaddey HL, Holder K (May 2014). "Unintentional weight loss in older adults". Am Fam Physician. 89 (9): 718–22. PMID 24784334.
- ↑ Morley JE, Kraenzle D (June 1994). "Causes of weight loss in a community nursing home". J Am Geriatr Soc. 42 (6): 583–5. doi:10.1111/j.1532-5415.1994.tb06853.x. PMID 8201141.
- ↑ Kondrup, J (2003). "ESPEN Guidelines for Nutrition Screening 2002". Clinical Nutrition. 22 (4): 415–421. doi:10.1016/S0261-5614(03)00098-0. ISSN 0261-5614.
- ↑ 4.0 4.1 Alsumali A, Eguale T, Bairdain S, Samnaliev M (August 2018). "Cost-Effectiveness Analysis of Bariatric Surgery for Morbid Obesity". Obes Surg. 28 (8): 2203–2214. doi:10.1007/s11695-017-3100-0. PMID 29335933.
- ↑ Ramachandran A (November 2014). "Know the signs and symptoms of diabetes". Indian J. Med. Res. 140 (5): 579–81. PMC 4311308. PMID 25579136.
- ↑ Mangili A, Murman DH, Zampini AM, Wanke CA (2006). "Nutrition and HIV infection: review of weight loss and wasting in the era of highly active antiretroviral therapy from the nutrition for healthy living cohort". Clin. Infect. Dis. 42 (6): 836–42. doi:10.1086/500398. PMID 16477562.
- ↑ Overactive thyroid and weight loss
- ↑ Tisdale MJ (April 2009). "Mechanisms of cancer cachexia". Physiol. Rev. 89 (2): 381–410. doi:10.1152/physrev.00016.2008. PMID 19342610.
- ↑ Mayo Clinic: Being Underweight Poses Health Risks. Retrieved January 13,2007
- ↑ Prevalence of various medical conditions increases with overweight and obesity
- ↑ Diabetes Study Shows Value In Diet, Exercise, September 2001
- ↑ Choosing a Safe and Successful Weight Loss Program
- ↑ 13.0 13.1 13.2 Bosch X, Monclús E, Escoda O, Guerra-García M, Moreno P, Guasch N, López-Soto A (2017). "Unintentional weight loss: Clinical characteristics and outcomes in a prospective cohort of 2677 patients". PLoS ONE. 12 (4): e0175125. doi:10.1371/journal.pone.0175125. PMC 5384681. PMID 28388637.
- ↑ Lankisch P, Gerzmann M, Gerzmann JF, Lehnick D (January 2001). "Unintentional weight loss: diagnosis and prognosis. The first prospective follow-up study from a secondary referral centre". J. Intern. Med. 249 (1): 41–6. doi:10.1046/j.1365-2796.2001.00771.x. PMID 11168783.
- ↑ 15.0 15.1 15.2 15.3 15.4 15.5 Alibhai SM, Greenwood C, Payette H (March 2005). "An approach to the management of unintentional weight loss in elderly people". CMAJ. 172 (6): 773–80. doi:10.1503/cmaj.1031527.
- ↑ Daly L, Dolan R, Power D, Ní Bhuachalla É, Sim W, Fallon M, Cushen S, Simmons C, McMillan DC, Laird BJ, Ryan A (February 2020). "The relationship between the BMI-adjusted weight loss grading system and quality of life in patients with incurable cancer". J Cachexia Sarcopenia Muscle. 11 (1): 160–168. doi:10.1002/jcsm.12499. PMC 7015235 Check
|pmc=value (help). PMID 31692296.
- ↑ Mascarenhas MR, Zemel B, Stallings VA (January 1998). "Nutritional assessment in pediatrics". Nutrition. 14 (1): 105–15. doi:10.1016/s0899-9007(97)00226-8. PMID 9437695.
- ↑ Guigoz, Yves; Vellas, Bruno; Garry, Philip J. (2009). "Assessing the Nutritional Status of the Elderly: The Mini Nutritional Assessment as Part of the Geriatric Evaluation". Nutrition Reviews. 54 (1): S59–S65. doi:10.1111/j.1753-4887.1996.tb03793.x. ISSN 0029-6643.
- ↑ 19.0 19.1 Purandare NC, Rangarajan V (2015). "Imaging of lung cancer: Implications on staging and management". Indian J Radiol Imaging. 25 (2): 109–20. doi:10.4103/0971-3026.155831. PMC 4419420. PMID 25969634.
- ↑ Goh Y, Dan YY, Chua W, Jagmohan P, Lee JK, Thian YL (2018). "Diagnostic utility of whole body CT scanning in patients with unexplained weight loss". PLoS ONE. 13 (7): e0200686. doi:10.1371/journal.pone.0200686. PMC 6063413. PMID 30052642.
- ↑ Huffman GB (February 2002). "Evaluating and treating unintentional weight loss in the elderly". Am Fam Physician. 65 (4): 640–50. PMID 11871682.
- ↑ Badowski ME, Yanful PK (2018). "Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer". Ther Clin Risk Manag. 14: 643–651. doi:10.2147/TCRM.S126849. PMC 5896684. PMID 29670357.
- ↑ Rusthoven J, Obrien B, Rocchi A (September 1992). "Ondansetron versus metoclopramide in the prevention of chemotherapy-induced nausea and vomiting - a metaanalysis". Int. J. Oncol. 1 (4): 443–50. doi:10.3892/ijo.1.4.443. PMID 21584565.
- ↑ Jaafar NR, Daud TI, Rahman FN, Baharudin A (September 2007). "Mirtazapine for anorexia nervosa with depression". Aust N Z J Psychiatry. 41 (9): 768–9. doi:10.1080/00048670701517983. PMID 17687663.
- ↑ Gulliford MC, Charlton J, Prevost T, Booth H, Fildes A, Ashworth M, Littlejohns P, Reddy M, Khan O, Rudisill C (January 2017). "Costs and Outcomes of Increasing Access to Bariatric Surgery: Cohort Study and Cost-Effectiveness Analysis Using Electronic Health Records". Value Health. 20 (1): 85–92. doi:10.1016/j.jval.2016.08.734. PMC 5338873. PMID 28212974.
- ↑ Warr DG, Grunberg SM, Gralla RJ, Hesketh PJ, Roila F, Wit R, Carides AD, Taylor A, Evans JK, Horgan KJ (June 2005). "The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials". Eur. J. Cancer. 41 (9): 1278–85. doi:10.1016/j.ejca.2005.01.024. PMID 15939263. Vancouver style error: initials (help)
- ↑ Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, Chawla SP, Carides AD, Ianus J, Elmer ME, Evans JK, Beck K, Reines S, Horgan KJ (November 2003). "The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group". J. Clin. Oncol. 21 (22): 4112–9. doi:10.1200/JCO.2003.01.095. PMID 14559886.
- ↑ Alibhai SM, Greenwood C, Payette H (March 2005). "An approach to the management of unintentional weight loss in elderly people". CMAJ. 172 (6): 773–80. doi:10.1503/cmaj.1031527. PMC 552892. PMID 15767612.