Approach to the patient with unintentional weight loss

INTRODUCTION — Weight loss is a common problem seen by generalists. Patients who are overweight or obese may intentionally lose weight to improve their health. However, progressive unintentional (involuntary) weight loss often indicates a serious medical or psychiatric illness.

This topic will discuss the approach to unintentional weight loss in the adult patient. Weight loss and nutritional issues in older adults and weight loss or inadequate weight gain in children and adolescents is discussed separately. (See "Geriatric nutrition: Nutritional issues in older adults" and "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation" and "Poor weight gain in children older than two years in resource-abundant settings".)

Weight loss in the management of obesity is also discussed separately. (See "Obesity in adults: Overview of management" and "Obesity in adults: Dietary therapy".)

DEFINITIONS

●Unintentional weight loss – Unintentional weight loss is also referred to as involuntary or unintended weight loss [1]. This term excludes weight loss as an expected consequence of treatment (eg, weight loss from diuretic therapy in patients with heart failure) or as a result of a known illness. Clinically important weight loss is generally defined as loss of more than 5 percent of usual body weight over 6 to 12 months [1,2].

Clinically significant weight loss and nutritional issues in older adult patients is discussed elsewhere. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Weight loss'.)

●Cachexia – Cachexia has varying definitions. It is generally defined as weight loss from loss of muscle mass (with or without fat loss). (See "Assessment and management of anorexia and cachexia in palliative care" and "Geriatric nutrition: Nutritional issues in older adults", section on 'Cachexia'.)

●Sarcopenia – Sarcopenia is a geriatric syndrome characterized by loss of muscle mass, strength, and performance [1]. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Sarcopenia'.)

EPIDEMIOLOGY — The majority of people will eventually meet the criteria for significant unintentional weight loss if they live long enough. It is estimated that 15 to 20 percent of adults ≥65 years have unintentional weight loss if followed over 5 to 10 years [3,4]. Up to 8 percent of outpatients will have unintentional weight loss. Many studies, especially of nursing home residents, report a prevalence of weight loss exceeding 50 percent, which is most commonly multifactorial and associated with functional decline [5,6].

There are fewer estimates of the incidence or prevalence of weight loss in the general population. The best evidence comes from survey studies. One survey including a representative sample of over 9000 adults in the United States found that 5 percent of participants reported unintentional weight loss of at least 5 percent of their usual body weight during the preceding year [7]. There were no important sex differences in weight loss incidence. The strongest independent predictors of unintentional weight loss were age, smoking, and poor self-reported health. In another United States survey including over 5000 participants age ≥50 years, 7 percent of the sample reported unintentional weight loss of 5 percent or more over six months [8]. Prevalence increased with age and was also higher among those with obesity.

MORTALITY AND OTHER HEALTH OUTCOMES — Unintentional weight loss is associated with increased mortality [9]. As examples:

●In a study of over 10,000 adult Israeli men, a 5 kg weight loss over five years without dieting was associated with an 18 percent increase in total mortality over the next 18 years [10]. The excess mortality was almost entirely explained by increased cardiovascular deaths, after adjusting for age, baseline cardiovascular risk factors, baseline body mass index (BMI), and other comorbidities. There was no increase in cancer mortality.

●In the United States National Health and Nutrition Examination Survey (NHANES) II Mortality Study, 5000 participants aged ≥50 years were followed for at least 12 years [8]. Unintentional weight loss was associated with a 24 percent relative increase in mortality during the follow-up period, even among those with obesity.

Mortality rates may be also increased for other specific populations with weight loss. As an example, weight loss among nursing home residents predicts increased mortality, regardless of underlying diagnosis [11-16]. Among patients with advanced lung disease and heart failure, those with weight loss also have increased mortality [17]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Weight loss and body mass index' and "Malnutrition in advanced lung disease", section on 'Effect on mortality and lung function'.)

In addition to higher mortality rates, unintentional weight loss is associated with an increased fracture risk and poor health related outcomes [18,19].

ETIOLOGIES — There are many causes of unintentional weight loss (table 1 and table 2). In the absence of fever or other cause for increased energy expenditure (eg, hyperthyroidism), weight loss is predominantly due to decreased food intake.

Progressive unintentional weight loss often indicates serious medical or psychiatric illness. Any chronic illness affecting any organ system can cause anorexia and weight loss. In studies that examined the etiologies for unintentional weight loss, malignancy is eventually identified as the primary cause in 15 to 37 percent of patients [15,20-23]. Nonmalignant gastrointestinal causes account for 10 to 20 percent [20,21,24,25]. Psychiatric causes occur in 10 to 23 percent of community-dwelling participants [20,21,23]. Up to 25 percent of cases have unknown causes [4,15,20].

At a diagnostic unit in Spain, 791 older adult patients were evaluated for unintentional weight loss without signs or symptoms specific to a particular etiology or organ system [26]. After one-year follow-up, 24 percent were diagnosed with malignancy, 45 percent with nonmalignant organic disease, 29 percent with psychiatric disease, and only 3 percent remained unexplained after one year of evaluation.

Malignancy — Malignancies (particularly gastrointestinal, pancreatic, lung, lymphoma, renal, and prostate cancers) often cause weight loss [27]. There are multiple mechanisms accounting for weight loss in patients with cancer. Anorexia and weight loss are present in 15 to 40 percent of all cancer patients at diagnosis [28], but the prevalence appears to be highest in those diagnosed with lung cancer (60 percent) or upper gastrointestinal cancer (80 percent) [28-30]. Cancer cachexia involves complex metabolic abnormalities that decrease muscle mass. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)

Among patients with unintentional weight loss, only a minority are subsequently diagnosed with malignancy. In a prospective cohort study from Spain, 2677 adults were systematically evaluated for unintentional weight loss and 902 (34 percent) were diagnosed with malignancy over the next five and a half years, although the vast majority of those (883) were diagnosed within the first six months of evaluation [15]. Among patients with unintentional weight loss, malignancy was associated with older age, male sex, active smoking, and greater weight loss. The most common malignancies in these patients were related to the gastrointestinal system (esophagus, stomach, bowel, liver, pancreas, biliary), lung, lymphoma, and urinary tract (kidney, ureter, bladder); cancers of the prostate, breast, and ovary were diagnosed much less frequently.

Patients with malignancy as a cause of unintentional weight loss often have one or more abnormalities (signs, symptoms, or laboratory abnormalities) noted during the initial diagnostic evaluation. For example, patients may have pain, abdominal distention, nausea, vomiting, dysphagia, early satiety due to hepatosplenic enlargement or malignant obstruction, hypercalcemia, or symptoms of malabsorption. (See 'Evaluation' below.)

In a prospective cohort study of 101 patients, all 22 patients with malignancy had an abnormal laboratory test, with C-reactive protein (CRP), hemoglobin, lactate dehydrogenase, and albumin having the highest sensitivities [31]. Abnormal abdominal ultrasound and chest radiograph had lower sensitivities of 45 and 18 percent, respectively. However, all of these diagnostic tests were also abnormal, but to a lesser extent, among patients with nonmalignant organic disease. Thus, there is no general diagnostic test or group of tests that appears to be specific for malignancy.

Nonmalignant gastrointestinal diseases — Numerous nonmalignant gastrointestinal etiologies can cause weight loss. Examples include peptic ulcer disease, diseases that cause malabsorption (eg, celiac disease), and inflammatory bowel disease (IBD).

Patients with weight loss from gastrointestinal causes will often have associated gastrointestinal symptoms including: anorexia, abdominal pain, early satiety, dysphagia, odynophagia, diarrhea, steatorrhea, chronic constipation, or evidence of chronic bleeding. They may also have signs and symptoms associated with chronic inflammation, chronic ischemia, obstruction, or fistulas. Patients with IBD may have extraintestinal manifestations (table 3). Patients with malabsorption may have weight loss with increased or normal appetite (table 4). (See "Approach to the adult patient with suspected malabsorption".)

Psychiatric disorders — Psychiatric disorders commonly cause weight loss. A prospective cohort study of 2677 patients with unintended weight loss found that 14 percent were the result of psychiatric disorders [15]. Among nursing home patients, psychiatric disorders, particularly depression, account for 31 to 58 percent of cases of unintentional weight loss [11,15,32,33].

●Depression – The independent role of depression in weight loss is difficult to determine due to the frequency of overlapping causes, such as social isolation, physical disabilities, dementia, dysphagia, medication/drug use, and multiple chronic diseases. (See "Unipolar depression in adults: Epidemiology".)

●Eating disorders – In patients who are of normal weight or underweight, obsession with being overweight leads to weight loss as a result of decreased food intake, excessive exercise, self-induced vomiting, drug/herbal medication use, and/or behaviors suggestive of bulimia/anorexia nervosa. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

●Other – Loss of appetite and unintentional weight loss can also occur in patients with other psychiatric disorders. During the manic phases of bipolar disorder, hyperactivity and preoccupations may interfere with normal eating patterns. In rare circumstances, patients with delusions or paranoia may develop peculiar ideations about food that lead to decreased food intake and subsequent weight loss. (See "Bipolar disorder in adults: Clinical features", section on 'Major depression' and "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation".)

Endocrinopathies — Weight loss is a common feature of endocrinopathies.

●Hyperthyroidism – Weight loss is a classic symptom of hyperthyroidism. Most patients have hyperphagia. Some younger patients with mild hyperthyroidism eat enough to actually gain weight. In older patients, however, hyperthyroidism often causes anorexia with accelerated weight loss. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●Diabetes mellitus – Uncontrolled diabetes mellitus can cause weight loss with increased appetite, particularly with new-onset type 1 diabetes mellitus. Although patients with poorly controlled or undiagnosed type 2 diabetes can occasionally present with weight loss, weight gain is much more common. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on 'Clinical presentation' and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Clinical presentation'.)

However, some patients with type 2 diabetes can occasionally present with diabetic neuropathic cachexia, an unusual and poorly understood syndrome characterized by profound weight loss (as much as 60 percent of body weight) and often severe neuropathic pain of the anterior thighs [34,35].

●Adrenal insufficiency – Chronic primary adrenal insufficiency often presents with significant weight loss, although other associated signs and symptoms are more prominent: dehydration, anorexia, lassitude, fatigue, and weakness. Adrenal insufficiency that is acute or due to hypothalamic or pituitary dysfunction is usually not associated with weight loss. (See "Clinical manifestations of adrenal insufficiency in adults".)

●Pheochromocytoma – The hyperadrenergic state among patients with pheochromocytoma would theoretically cause weight loss with increased appetite, but only 5 percent of patients with pheochromocytomas report weight loss [36]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Less common symptoms and signs'.)

Infectious diseases — Many chronic infections lead to unintentional weight loss. As examples:

●HIV – Patients with HIV infection have total daily energy expenditure similar to normal subjects [37-39]. Weight loss in patients with HIV infection is usually episodic, occurring with secondary infections or gastrointestinal diseases, and leads to a reduction in energy intake. The lethargy and fatigue that accompany infection may help maintain energy balance and weight [39].

●Tuberculosis – Many patients with active tuberculosis experience weight loss. For reactivation tuberculosis, significant weight loss is one of the cardinal signs and symptoms. (See "Pulmonary tuberculosis: Clinical manifestations and complications".)

●Hepatitis C – Chronic infection with hepatitis C virus can also cause weight loss, in addition to nausea, anorexia, and weakness. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Generalized symptoms'.)

●Helminthic infections – A number of helminthic infections can cause nutritional deficiencies and weight loss. Specific helminth infections are discussed in the appropriate topics.

Advanced chronic disease — Advanced chronic cardiac, lung, or renal disease are all associated with weight loss.

●Congestive heart failure – Nearly one-half of heart failure patients with New York Heart Association Class III or IV disease lose lean body mass and meet criteria for malnutrition. Weight loss in this population can be associated with anorexia, early satiety, depression, intestinal and liver congestion, and increased levels of cytokines and angiotensin II [40]. The fluid retention associated with chronic heart failure often masks the extensive loss of lean body mass. Weight loss in patients with chronic heart failure is associated with an increased mortality rate. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Weight loss and body mass index'.)

●Chronic lung disease (pulmonary cachexia syndrome) – Chronic weight loss with malnutrition can occur with severe chronic lung disease and has been called the pulmonary cachexia syndrome. Estimates of cachexia in severe chronic obstructive pulmonary disease range from 30 to 70 percent [41]. Progressive weight loss can occur even with adequate caloric intake due to increased respiratory muscle work and possibly systemic inflammation. Often the weight loss is episodic, associated with exacerbations of lung disease, but without any regain in weight after recovery. Glucocorticoid treatment, systemic inflammation, and immobility contribute to the loss of muscle mass in severe lung disease. (See "Malnutrition in advanced lung disease", section on 'Metabolism and caloric intake'.)

●Advanced kidney disease – In advanced kidney disease, anorexia and other uremic symptoms usually occur when the glomerular filtration rate (GFR) drops below 15 mL/min. As with heart failure, fluid retention in advanced kidney disease often masks the true loss in lean body mass. (See "Overview of the management of chronic kidney disease in adults", section on 'Malnutrition'.)

Neurologic diseases — Several neurologic illnesses, including stroke, dementia, Parkinson disease, and amyotrophic lateral sclerosis, can lead to weight loss. Weight loss may be due to one or more deficits, such as altered cognition, motor dysfunction, and dysphagia, associated with these disorders. (See "Complications of stroke: An overview" and "Clinical manifestations of Parkinson disease" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

In a prospective cohort study of 1900 people, a decline from midlife weight was associated with an increased risk of mild cognitive impairment [42]. (See "Risk factors for cognitive decline and dementia", section on 'Obesity and body mass index'.)

Medications/substances — Over-the-counter, prescription, and illicit drugs can lead to weight loss (table 1 and table 5). Weight loss is a known adverse effect of several common prescription drugs, including anticonvulsants (table 6), diabetes medications (table 7), and thyroid medication. Importantly, cholinesterase inhibitors used to treat dementia (eg, donepezil, rivastigmine, galantamine) may contribute to weight loss. A meta-analysis of 25 studies with over 10,000 patients demonstrated that participants taking cholinesterase inhibitors had an increased likelihood of weight loss [43]. Marked weight loss can occur after reduction or withdrawal of some antipsychotic drugs (eg, chlorpromazine, haloperidol, thioridazine, mesoridazine) [44]. Patients who experience weight loss have usually been treated for many years with high doses. Weight loss with withdrawal of newer antipsychotic agents occurs infrequently.

Weight loss also occurs with several drugs of abuse:

●Alcohol – Many alcohol-dependent patients consume most of their calories from alcohol and thus have several nutritional deficiencies in addition to weight loss. However, weight loss in patients with alcoholic cirrhosis may be masked by secondary ascites and fluid retention. (See "Nutritional status in patients with sustained heavy alcohol use".)

●Cocaine – As many as 40 percent of chronic cocaine users experience weight loss, anorexia, and sleep disturbances. (See "Cocaine use disorder: Epidemiology, clinical features, and diagnosis".)

●Amphetamines – Amphetamines promote release of catecholamines from presynaptic nerve terminals, which can decrease appetite and increase basal metabolism. (See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

●Marijuana – Withdrawal from chronic marijuana use can cause a syndrome that includes anorexia, weight loss, irritability, and strange dreams [45].

●Tobacco – Heavy tobacco use leads to weight loss, whereas weight gain occurs with smoking cessation. (See "Benefits and consequences of smoking cessation", section on 'Weight gain'.)

Rheumatologic — Patients with rheumatologic conditions (eg, rheumatoid arthritis, giant cell [temporal] arteritis) often have weight loss as part of systemic symptoms. There are also reports of older patients with unintentional weight loss who are eventually diagnosed with giant cell arteritis but never manifest classic signs or symptoms of the disease [46]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Initial clinical presentation' and "Clinical manifestations of giant cell arteritis", section on 'Constitutional symptoms'.)

Other

●Social factors leading to inadequate dietary intake – Patients may have weight loss from inadequate dietary intake due to social factors (eg, inability to obtain food), particularly in older adult patients. (See 'Psychiatric disorders' above and "Geriatric nutrition: Nutritional issues in older adults", section on 'Social factors'.)

●Athletes – Some persons have vocations that require them to be very lean (eg, long-distance runners, models, ballet dancers, gymnasts). Some persons who engage in intense training must increase their intake of calories considerably to maintain their weight and muscle mass. Increased food intake is not always sufficient to maintain body weight, resulting in transient or persistent weight loss. (See "Exercise physiology".)

EVALUATION — The electronic health record may be used to automatically identify patients with 5 percent or greater weight loss to trigger the clinician to investigate the cause. Given the broad differential diagnosis of unintentional weight loss (table 1), there is no single diagnostic approach for all patients. The evaluation should begin with verification of the weight loss (patients may complain of weight loss without an objective weight loss), followed by a careful history and physical examination (algorithm 1). The workup should be individualized, based on findings from the history and examination [47].

A study in the United Kingdom. using electronic records of five million primary care patients in the National Health Service (2000 to 2012) was performed to identify which diseases warranted a focused evaluation for patients identified with unintentional weight loss, based on patient age and sex [48]. The most beneficial evaluation for men and women under age 60-years was for depression, diabetes, and hyperthyroidism. For men age 60- to 80-years-old, the most beneficial evaluation was for malignancy, diabetes, and chronic lung disease; for women age 60- to 80-years-old, thyroid disease, depression, and malignancy; and for patients older than 80 years-old, malignancy, dementia, depression, and heart failure.

Patients with <5 percent loss of usual body weight can be closely followed; the interval of follow-up may vary depending on the patient’s age and comorbidities.

In patients with documented weight loss of ≥5 percent of usual body weight and positive findings on history or physical examination, further testing should be focused on confirming the suspected diagnosis. There are no widely accepted guidelines for the clinical evaluation of unintentional weight loss.

History — The history of a patient with unintentional weight loss includes documenting the weight loss, assessing the pattern of weight loss, evaluating for eating disorders and possible occult intentional weight loss, and evaluating the consequences of the weight loss (such as malnutrition).

●Documenting weight loss – Qualitative judgments by patients about the magnitude of their weight loss are often unreliable. In a prospective study of unintentional weight loss, only 50 percent of patients reporting weight loss had true weight loss [24]. Therefore, it is important to obtain previous weight records and, if not available, to query family members about the patient's weight history, including usual weight prior to the period of weight loss. Unintentional weight loss exceeding 20 percent of usual weight is often associated with severe protein-energy malnutrition, nutritional deficiencies, and multiorgan dysfunction [49].

●Pattern of weight loss – It is important to determine the duration and pattern of weight loss, including past fluctuations in weight and whether weight loss is progressive or stable. Recent weight loss in a person whose weight has been stable for many years, and weight loss that is progressive, are more worrisome and require more immediate follow-up. For example, an unintentional weight loss of greater than 10 percent of body weight over one year is seen among 11 percent of those newly diagnosed with cancer or liver disease and in 9 percent of those newly diagnosed with cardiovascular or respiratory disease [50]. Other factors to consider in weight loss pattern include changes in appetite, caloric intake, and physical activity.

●Evaluation for eating disorders and intentional weight loss – Clinicians should question patients regarding possible intentional weight loss from dieting. An analysis of the United States National Health and Nutrition Examination Survey (NHANES) data identified a recent diagnosis of diabetes as predicting a 12 percent chance of intentionally losing at least 10 percent of body weight over the next year [50]. Patients should also be assessed for intentional weight loss from eating disorders. A number of screening instruments have been developed to identify patients with eating disorders. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis", section on 'Screening'.)

The clinical features of anorexia nervosa include restriction of energy intake leading to an abnormal body weight, intense fear of gaining weight or becoming fat, and distorted perception of body weight and shape. Clinical features of bulimia include binge eating, inappropriate compensatory behavior to prevent weight gain (eg, self-induced vomiting), and excessive concern about body weight and shape. (See "Anorexia nervosa in adults: Clinical features, course of illness, assessment, and diagnosis", section on 'Clinical features' and "Bulimia nervosa in adults: Clinical features, course of illness, assessment, and diagnosis", section on 'Clinical features'.)

●Malnutrition screening – There are several validated screening tools to help identify patients at risk for malnutrition, all of which include a measure of unintentional weight loss. Using one of these tools over time and across settings may avoid malnutrition and improve patient outcomes [51,52].

It is also important to elicit associated symptoms, medications, as well as functional and social factors associated with poor food intake [4,16]:

●Associated symptoms – We ask all patients about other gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, dysphagia, diarrhea, and bloody or dark stools. Additionally, we assess all patients for symptoms of:

•Malignancy – Patients may have night sweats, fevers, and fatigue. Patients should also be assessed for symptoms of malignancy based on age and risk factors (eg, asking about bloody or dark stools in patients ≥50 years or at risk for colon cancer, or pulmonary symptoms in patients who are smokers or former smokers).

•Malabsorption – Symptoms of malabsorption include steatorrhea, muscle loss, watery diarrhea (table 4). Patients may also have symptoms of nutritional deficiency associated with malabsorption (eg, increased bruising from vitamin K deficiency (table 4)).

•Psychiatric disorders – Patients should be assessed for psychiatric disorders, particularly depression. The two-item Patient Health Questionnaire (PHQ), either as a verbal or written screen, is easily administered with reasonable performance characteristics (table 8). A positive screen should be followed by a clinical interview, facilitated with the PHQ-9 (table 9) or a similar instrument, to diagnose depression. (See 'Psychiatric disorders' above and "Screening for depression in adults".)

●Medications/substances – Many medications and substances can affect weight (table 1 and table 5). Taking a careful history is important in identifying all medications (including nonprescription medications and herbal remedies), medication changes, and any substance use. (See 'Medications/substances' above.)

●Functional factors – Functional factors such as dysphagia, poor dentition, or poor cognition/dementia may contribute to weight loss.

●Social factors – We ask patients to describe their diet and ask about social factors related to food (eg, how the patient gets food, who cooks). Certain diseases have different micronutrient needs that may not be met by normal diets [53]. In appropriate patients, we also ask about travel history and sexual history to assess risk for infectious etiologies. (See 'Infectious diseases' above.)

A thorough review of systems is necessary if the etiology remains uncertain after the above questioning.

Physical examination — The physical examination focuses on evaluating for symptoms of the various etiologies of unintentional weight loss, including psychiatric disorders, hyperthyroidism, nutritional deficiencies, and chronic disease. We pay particular attention to:

●General appearance – Patients may have a flat affect which can be a sign of psychiatric disease.

●Head and neck – Patients should be examined for ophthalmoplegia and stigmata of nutritional deficiencies (eg, cheilosis, glossitis) (table 4). If appropriate, a dental examination should be done as poor dentition can lead to weight loss.

●Cardiopulmonary examination – Patients with chronic cardiac and pulmonary disease may have weight loss.

●Abdominal examination – Patients should be assessed for abdominal tenderness, ascites, hepatosplenomegaly, and abdominal masses. (See "Evaluation of the adult with abdominal pain", section on 'Physical examination'.)

●Cognitive and neurologic exam – We perform a neurologic exam to evaluate for deficits. Also, particularly in older patients, we assess for cognitive impairment and dementia as these can contribute to weight loss. (See "Evaluation of cognitive impairment and dementia".)

●Other – We also examine for lymphadenopathy.

Several prospective studies have verified the importance of a complete physical examination in evaluating unexplained weight loss [24,31,54]. In observational studies, abnormal physical findings were common among those with malignancy [20,31,54]. As an example, in a prospective cohort study of 101 patients, 12 out of 22 patients (55 percent) diagnosed with cancer as the cause of weight loss had an abnormal physical examination finding [31]. In another study, abnormal physical findings were found among 59 percent of patients who were diagnosed with either malignancy or other organic causes of weight loss [54]. Conversely, abnormal physical findings were present in only 3 percent of those diagnosed with a psychiatric disorder or who remained undiagnosed after a thorough evaluation and follow-up.

Diagnostic testing — In patients with documented weight loss of ≥5 percent of usual body weight and positive findings on history or physical examination, further testing should be focused on confirming the suspected diagnosis (algorithm 1). Patients with history or physical examination (table 4) concerning for malabsorption should be evaluated appropriately. (See "Approach to the adult patient with suspected malabsorption", section on 'Additional evaluation to determine the underlying etiology'.)

When the history and physical examination do not indicate a likely diagnosis, basic diagnostic testing will yield a diagnosis in the majority of cases [3-5,22,24,31]. Subsequent diagnostic testing will depend on initial tests. A basic diagnostic evaluation should include:

●Complete blood count with differential (see "Diagnostic approach to anemia in adults" and "Approach to the patient with neutrophilia" and "Approach to the patient with unexplained eosinophilia")

●Electrolytes (see "Causes of hypotonic hyponatremia in adults" and "Etiology and evaluation of hypernatremia in adults" and "Causes and evaluation of hyperkalemia in adults" and "Causes of hypokalemia in adults")

●Glucose and hemoglobin A1c (see "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults")

●Calcium (see "Diagnostic approach to hypercalcemia" and "Etiology of hypocalcemia in adults")

●Renal function and urinalysis (see "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Urinalysis in the diagnosis of kidney disease")

●Hepatic function (see "Approach to the patient with abnormal liver biochemical and function tests")

●Thyroid-stimulating hormone (see "Laboratory assessment of thyroid function")

●Stool Hemoccult (see "Evaluation of occult gastrointestinal bleeding")

●Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) (see "Acute phase reactants")

●Human immunodeficiency virus (HIV) (see "Screening and diagnostic testing for HIV infection")

●Hepatitis C in patients with risk factors (table 10) (see "Screening and diagnosis of chronic hepatitis C virus infection")

●Chest radiograph (for tuberculosis or malignancy)

●Age-appropriate cancer screening (see "Overview of preventive care in adults", section on 'Cancer screening' and "Geriatric health maintenance", section on 'Cancer screening')

Follow-up — Despite an appropriate initial evaluation, a clear cause for weight loss may not be found. If no abnormality is identified after initial evaluation, watchful waiting for one to six months is preferable to a battery of testing with low diagnostic yield (algorithm 1). As organic disease is rarely found in patients with a normal physical examination and normal initial diagnostic testing, a waiting period of one to six months is unlikely to result in an adverse outcome [5,24,55]. On follow-up, careful attention should be paid to dietary history, possibility of psychosocial causes, surreptitious drug intake, and new manifestations of occult illness. Patients with progressive weight loss that is documented over multiple visits (versus stabilized weight loss) should be seen in a shorter time frame. Further evaluation for malignancy in older patients may be reasonable and is discussed elsewhere. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Subsequent evaluation'.)

SUMMARY AND RECOMMENDATIONS

●Definition – Clinically important weight loss is generally defined as loss of more than 5 percent of usual body weight over 6 to 12 months. (See 'Definitions' above.)

●Importance – Unintentional weight loss is associated with increased mortality rates. (See 'Mortality and other health outcomes' above.)

●Causes – There are many causes of weight loss (table 1 and table 2). Progressive unintentional weight loss often indicates serious medical or psychiatric illness. (See 'Etiologies' above.)

●History and physical examination – Given the broad differential diagnosis of unintentional weight loss (table 1), there is no single diagnostic approach for all patients. The evaluation should start with verifying the weight loss followed by a careful history and physical examination (algorithm 1). Many patients who complain of weight loss do not have documented weight loss. (See 'Evaluation' above.)

•The history of a patient with unintentional weight loss includes documenting the weight loss, assessing its pattern, evaluating for eating disorders and possible intentional weight loss, and eliciting other factors that may be related to the weight loss. (See 'History' above.)

•The physical examination focuses on evaluating for signs of the various etiologies of unintentional weight loss, including psychiatric disorders, hyperthyroidism, nutritional deficiencies, and undiagnosed chronic diseases. (See 'Physical examination' above.)

●Further evaluation – The workup of a patient with unintentional weight loss should be individualized based on findings from the patient's history and physical examination (algorithm 1). (See 'Evaluation' above.)

•In patients with documented weight loss of ≥5 percent of usual body weight and findings on history or physical examination, further testing should be focused on confirming the suspected diagnosis. Patients with history or physical examination (table 4) concerning for malabsorption should be evaluated appropriately. (See "Approach to the adult patient with suspected malabsorption", section on 'Initial evaluation'.)

•When the history and physical examination do not indicate a likely diagnosis, a basic diagnostic evaluation should include complete blood count with differential, electrolytes, glucose, hemoglobin A1c, calcium, renal and hepatic function tests, thyroid-stimulating hormone, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), urinalysis, stool for occult blood, human immunodeficiency virus (HIV) serology, hepatitis C serology in patients with risk factors (table 10), chest radiograph, and age-appropriate cancer screening. Further evaluation should be based on results of these initial tests. (See 'Diagnostic testing' above.)

•If no abnormality is identified on initial evaluation, a watchful waiting approach can be taken and the patient reassessed in one to six months. (See 'Follow-up' above.)