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.  It is a diagnostic challenge because, while an underlying illness may be found after a thorough history and physical exam, the etiology may also 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.         Similarly, 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.  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. 
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.    For patients with the most clinically applicable presentation (i.e., weight loss occurring within the preceding 6 months), the prevalence is approximately 7%.  An association with mortality and unintentional weight loss has been demonstrated in epidemiologic studies of overweight and obese subjects,  and in older patients with unintentional (but not intentional) weight loss.  In patients with recent (i.e., within 6 months) unintentional weight loss, weight loss of 5% or greater was associated with an increase in subsequent mortality.  Unintentional weight loss has been associated with increased perioperative complications in patients undergoing colorectal surgery and surgery for disseminated cancer.  
Unintentional weight loss mounts 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. 
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.  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.   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.
The differential diagnosis is extremely broad. In case series, the most common etiologies are:
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
Social factors that prevent adequate access to food.
Division of General Internal Medicine
Department of Medicine
University of Washington
CJW is an author of a reference cited in this monograph. He also receives royalties from Springer for a textbook on perioperative medicine.
Western General Hospital
AS declares that he has no competing interests.
Professor of Medicine
Medical Director, Endoscopy
Section of Gastroenterology/Hepatology
Georgia Regents University-Medical College of Georgia
SMC declares that he has no competing interests.
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