Evaluation of Weight Loss
Involuntary weight loss, which can be defined as an unexplained sustained weight loss of 5% or more over a 6- to 12-month period, is a sensitive, although nonspecific, complaint, which can be a harbinger of serious underlying pathology and poor prognosis, especially in the elderly. Problematic weight loss in the older adult is defined in nursing home legislation as a loss of 5% of body weight in 1 month or 10% over a period of 6 months or longer. Unintentional weight loss of more than 5% in a year is an independent predictor of increased mortality. Reports of prevalence for unintentional weight loss range from 3% to 10%, with frequency greatest among the elderly.
Unexplained weight loss often suggests the presence of worrisome underlying pathology, yet a substantial fraction of patients turns out to be free of serious organic illness. For example, in a series of patients with involuntary weight loss followed for 1 year, 50% either died or deteriorated during the course of the study; however, another 35% were well at the time of follow-up. Involuntary weight loss in excess of 2.5 kg (about 5.5 lb) over 6 to 12 months is usually considered
a reasonable threshold for initial evaluation because more than 95% of patients with an organic etiology will have lost at least that much weight.
a reasonable threshold for initial evaluation because more than 95% of patients with an organic etiology will have lost at least that much weight.
Unless extreme, the amount of weight loss is not necessarily predictive of an organic etiology or poor outcome. However, one or more episodes of unintentional weight loss of more than 20 lb during adulthood are associated with a 50% increase in risk of death. In many cases of weight loss, accompanying symptoms readily suggest the cause, but when a marked fall in weight is the sole or predominant complaint, the assessment can be difficult. Underlying malignancy, chronic inflammatory disease, serious infection, and depression represent primary concerns. The problem is of particular concern in the frail elderly. In the long-term care setting, those who lose 5% or more of their body weight within 1 month are 4.6 times more likely to die within 1 year. Unintentional weight loss also appears to be associated with an increased risk of death among communitydwelling older adults.
The initial evaluation by the primary care physician focuses on making an etiologic diagnosis and determining by history and physical examination who requires a more extensive medical evaluation and who can be managed empirically.
Pathophysiology
Involuntary weight loss represents a state of malnutrition, which can be subdivided pathophysiologically into mechanisms of starvation and cachexia. Although frank clinical states of starvation or cachexia are often not evident, one of these pathophysiologic mechanisms is likely to be operational in cases of involuntary weight loss. In both, there is reduced caloric intake resulting in weight loss, but in starvation, resting energy expenditure, protein synthesis, and protein degradation are reduced, whereas in cachexia, these parameters are markedly increased. In starvation, fat is lost preferentially; in cachexia, loss of muscle mass is prominent.
Cachexia
The pathophysiology of cachexia starts with tissue injury triggering the release of proinflammatory cytokines (e.g., interleukins, tumor necrosis factor), which in turn stimulate synthesis of binding proteins, complement, apoproteins, fibrinogen, C-reactive protein, and other inflammatory mediators. Skeletal muscle is sacrificed to provide the essential amino acids needed to support the increased protein synthesis. Resting metabolism increases to supply the additional energy necessary for proteolysis and synthesis of new protein. Cytokine release also reduces appetite and contributes to the anorexia and fatigue that are prominent in conditions associated with cachexia.
Starvation
In contrast, starvation’s pathophysiology entails mobilization and metabolism of stored fat in conjunction with reductions in energy expenditure, protein synthesis, and protein degradation.
Caloric Deficit and Volume Depletion
Regardless of underlying pathophysiology, caloric deficit is a common denominator in cases of weight loss, initially targeting fat stores. The principal mechanisms resulting in caloric deficits are reduced food intake, malabsorption, excess nutrient loss, and increased caloric requirements. When the number of calories available for utilization falls below daily needs, weight is lost; 1 lb of fat is consumed for every 3,500-cal deficit. Loss of fluid and dehydration will also register as a fall in weight, with about 1 kg (2.2 lb) lost for every liter removed and not replaced.
Anorexia
The mechanisms of anorexia include those associated with the pathologic conditions leading to cachexia (see earlier) as well as with polypharmacy, pain, and depression (e.g., increased corticotropin-releasing factor). In the elderly, the normal physiology of aging may contribute, producing reductions in smell and taste and increases in the appetite-suppressing hormones leptin (from decreased testosterone) and cholecystokinin. Moreover, there is less gastric distensibility (producing early satiety) and more social isolation. Unpalatable diets, especially those that are very low in sodium, may contribute.
Clinical Presentation
Although the clinical features of the underlying etiology usually dominate the presentation, a few features may suggest the underlying pathophysiology. For example, disproportionate loss of muscle mass and increased resting heart rate suggest cachexia, whereas relative preservation of muscle mass and a slow pulse suggest starvation. Reduced intake is suggested clinically by anorexia or disinterest in food. Malabsorption can cause foul-smelling, bulky, greasy stools in advanced cases; subtle changes in stool consistency and frequency are noted earlier (see Chapter 64). Excessive loss may present as recurrent vomiting, profuse diarrhea, polyuria, or fistulous drainage. Increased demand may be manifested by signs of underlying infection, inflammation, metabolic excess, or malignancy.
Although many of the illnesses that cause weight loss produce readily evident clinical manifestations, some conditions have presentations that are notoriously subtle and may involve little more than unexplained weight loss and vague systemic or functional complaints. These deserve special elaboration.
Major Depression
Major depression is the leading cause of unexplained weight loss, especially in the elderly, in whom the condition accounts for up to 30% of cases. As frequent as it is, depression is often overlooked unless specifically considered. Somatic manifestations include appetite disturbance, early-morning awakening, multiple bodily complaints, and fatigue; anhedonia, low selfesteem, feelings of guilt, and suicidal thoughts are among the characteristic psychological features. The death of a loved one, social isolation, and poverty are important psychosocial precipitants (see Chapter 227).
Dementia
Dementia is an increasingly important etiology of weight loss in the frail elderly and often contributes to social isolation and depression. Early manifestations may be subtle and include cessation of regular shopping and failure to prepare meals or to come to dinner in social settings (see Chapter 173).
Eating Disorders
Eating disorders often involve covert behaviors. The patient suffering from anorexia nervosa may deny any disturbance of appetite yet persist in restricting food intake to the point of cachexia. Prevalence is highest among adolescent girls and young women. They decide to diet to an extreme degree, are preoccupied with a phobic concern about being fat, and are
motivated by a relentless pursuit of thinness. Dieting persists because its psychological gratifications outweigh those derived from the intake of food. Paradoxically, the patient often reports feeling well and initially appears bright and undisturbed by the weight loss; anorexia is usually denied. At times, a few specific foods are the only ones consumed (e.g., vegetable juices). Amenorrhea is invariable and appears shortly after weight loss begins. A variant of anorexia nervosa consists of surreptitiously induced vomiting following engorgement with food; hypokalemic alkalosis results (see Chapter 234).
motivated by a relentless pursuit of thinness. Dieting persists because its psychological gratifications outweigh those derived from the intake of food. Paradoxically, the patient often reports feeling well and initially appears bright and undisturbed by the weight loss; anorexia is usually denied. At times, a few specific foods are the only ones consumed (e.g., vegetable juices). Amenorrhea is invariable and appears shortly after weight loss begins. A variant of anorexia nervosa consists of surreptitiously induced vomiting following engorgement with food; hypokalemic alkalosis results (see Chapter 234).
Carcinoma of the Pancreas
Carcinoma of the pancreas is the prototypical occult neoplasm associated with dramatic weight loss. Weight loss is found in 79% to 90% of patients at the time of diagnosis and averages 15 to 20 lb. The degree of weight loss does not seem to correlate with size, location, or extent of disease. Aversion to food is more typical of this malignancy than is true anorexia. In many instances, weight loss precedes all other symptoms; once jaundice and abdominal pain supervene, the tumor is usually far advanced. Many other gastrointestinal malignancies as well as ovarian cancer may follow a similar clinical course.
HIV Infection
HIV infection can result in profound weight loss. There may be inadequate intake resulting from dysphagia, depression, or medication. Early satiety can result from gastrointestinal invasion by lymphoma, Kaposi sarcoma, or Mycobacterium avium-intracellulare infection. Weight loss in the setting of adequate caloric intake suggests disseminated infection by M. avium-intracellulare or cytomegalovirus as well as occult malignancy. Often, the later stages of AIDS are characterized by a wasting syndrome, which includes loss of more than 10% of baseline weight, recurrent fever, and persistent diarrhea. The pathophysiologic mechanisms of cachexia (see earlier discussion) may play important roles, as might hypogonadism (see Chapter 13).
Celiac Sprue
Celiac sprue and other gastrointestinal causes of malabsorption may present nonspecifically in their early phases with subtle weight loss and vague gastrointestinal or extraintestinal complaints. The textbook presentation of steatorrhea may not become evident until much later. Common manifestations include modest weight loss, unexplained iron deficiency anemia, aphthous stomatitis, malaise, fatigue, nocturnal diarrhea, flatulence, and lactose deficiency (see Chapter 64). Stools are noted to be a bit softer and more frequent than usual, and a diagnosis of irritable bowel syndrome may be entertained mistakenly because of abdominal discomfort and bloating. Mild forms of inflammatory bowel disease may also be mistaken for irritable bowel syndrome (see Chapter 64).
Early Crohn Disease
Early Crohn disease in adolescents has been noted on occasion to begin inconspicuously with anorexia predominating. Blind loop syndrome and giardiasis may also have indolent presentations with weight loss and vague abdominal discomfort; however, changes in stools are usually present also, with patients reporting mushy, foul-smelling bowel movements (see Chapter 58).
Diabetes Mellitus
Diabetes mellitus is commonly found in overweight adults, but it may be the cause of weight loss when there is substantial wasting of calories from marked glycosuria. In addition, young male insulin-dependent diabetic patients are sometimes plagued by diarrhea, which exacerbates fluid and nutrient losses; true malabsorption has been noted in a few cases (see Chapter 102).
Hyperthyroidism
Hyperthyroidism that is clinically overt is an obvious cause of weight loss due to increased caloric demand; however, apathetic hyperthyroidism of the elderly may be mistaken for malignancy because weight loss is profound and the patient appears listless. The typical symptoms of excess thyroid hormone are absent, and unexplained atrial fibrillation is often present (see Chapter 103).
Vasculitis
Vasculitis, like HIV infection, is an archetypical example of unexplained weight loss due to tissue injury and cachexic pathophysiology. Resting metabolism is increased due to stepped-up synthesis of cytokines and other immunomodulators. A host of nonspecific systemic symptoms may predominate, triggered by the high circulating levels of these inflammatory mediators. Low-grade fever, malaise, anorexia, night sweats, apathy, and even depression may predominate. High levels of C-reactive protein and a markedly elevated erythrocyte sedimentation rate are characteristic and important clues to the diagnosis. More specific symptoms and signs suggesting the underlying etiology include palpable purpura, joint swelling and warmth, cranial artery tenderness, microscopic hematuria, and proteinuria (see Chapters 161 and 179).
Patients with an underlying medical cause for their weight loss usually present with symptoms and signs that strongly suggest organic illness. In a Veterans Administration study of 91 patients with involuntary weight loss, the cause in the overwhelming majority was readily diagnosed on the basis of the initial history and physical examination; only 1 patient had a truly occult malignancy (see later discussion).
The extensive list of causes of involuntary weight loss can be grouped pathophysiologically. Decreased intake, impaired absorption, increased loss, and excess demand are the principal mechanisms around which the differential can be organized (Table 9-1). Almost any illness can cause involuntary weight loss; Table 9-1 emphasizes those conditions seen in the ambulatory setting that may present as unexplained loss of weight. Studies from primary care practices find depression to be the leading cause of unexplained weight loss, with prevalence reported in the range of 15% to 30%. Among the elderly, psychosocial factors such as loss of a spouse, social isolation, and poverty can exacerbate inadequate food intake resulting from depression. Occult malignancy, although much feared in the elderly, is usually a distant runner-up, with half the prevalence of depression. In some series, therapeutic diets, particularly those for hyperlipidemia and diabetes, also rank high in the list of causes, followed by uncontrolled diabetes and oropharyngeal problems. In the elderly, immobility, poor dentition, dementia, side effects of medication, and a decrease in sense of taste are additional causative factors that require consideration.
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