Weight loss in the absence of deliberate dieting is a more serious problem than weight gain because there is a high chance that organic disease is present. Mechanisms include decreased appetite, accelerated metabolism, and loss of calories in urine or stool, acting singly or in combination. No attempt will be made to list all diseases capable of causing weight loss, but in one prospective study 26 percent of patients had no identifiable physical or psychiatric illness to which the weight loss could be attributed. If uncontrolled and symptomatic, any serious illness can cause weight loss; the usual mechanism is anorexia due either to direct pathophysiologic consequences (e.g., congestion of the liver and gastrointestinal tract in right-sided heart failure) or malaise and depression. The following categories are singled out for special comment because the primary illness may be masked at the time of initial presentation.
Initial weight loss with the onset of diabetes is largely fluid and is due to the osmotic diuresis induced by hyperglycemia. Subsequently, loss of tissue mass occurs in the insulin-dependent form of the disease as a result of caloric wastage (the consequence of glycosuria) and of the hormonal abnormalities that characterize the illness. Insulin deficiency and glucagon excess result in impaired synthesis of protein and fat and simultaneously cause accelerated proteolysis and lipolysis such that the net energy state is catabolic. Weight loss in diabetes is frequently associated with increased food intake.
While weight loss is not inevitable (indeed, thyrotoxicosis may rarely be found in a patient who has gained weight), it is common in hyperthyroidism. Increased appetite and food intake are the rule, and patients often consume a high-carbohydrate diet. Caloric expenditure is enormous, primarily because of an increased metabolic rate, but increased motor activity also plays a role. The molecular mechanism whereby thyrotoxicosis causes weight loss is not settled, but thyroid hormone is thought to increase sodium-potassium adenosine triphosphatase (ATPase) activity in many tissues, suggesting that the diminished efficiency of ingested calories is due to futile cycle of adenosine triphosphate (ATP) synthesis and breakdown with energy lost as heat. In “apathetic” hyperthyroidism weight loss and weakness may predominate with little evidence of nervousness or other symptoms. Another cause of weight loss due to hypermetabolism is pheochromocytoma, the inducing agent being catecholamine release. Panhypopituitarism and adrenal insufficiency may also be associated with weight loss, largely as a consequence of diminished appetite secondary to Cortisol deficiency.
Overt or occult steatorrhea due to sprue, chronic pancreatitis, or cystic fibrosis may produce wasting despite major increases in food intake. Chronic diarrhea due to inflammatory bowel disease (with or without fistulas) or parasites, esophageal disease with reflux or vomiting, and even ordinary peptic ulcer have to be considered in the differential diagnosis. The mechanism of weight loss in alimentary tract disease is generally either decreased food intake or malabsorption, though inflammation per se probably plays a role in the weight loss of ulcerative colitis and regional enteritis.
Hidden infection must always be sought in patients with unexplained weight loss. Tuberculosis, fungal disease, amebic abscess, and subacute bacterial endocarditis should be high on the list of suspects. The mechanism probably involves both anorexia and inflammation-induced acceleration of cellular metabolic demands. Glucagon may play a role in the negative nitrogen balance and tissue wastage of inflammation, but the catabolic state probably also requires changes in other hormones.
Occult malignancy is probably the most common cause of weight loss in the absence of major signs and symptoms. In the search for malignancy particular emphasis must be placed on the gastrointestinal tract, pancreas, and liver. Lymphoma and leukemia should also be considered. While silent (except for weight loss) malignancy can occur in any organ, the gastrointestinal tract is the most common site. Mechanisms of weight loss in cancer vary, and more than one factor often plays a role. For example, although anorexia is almost invariably present in carcinoma of the pancreas, malabsorption appears to play the predominant role, with weight gain frequently occurring when pancreatic enzymes are provided. In other tumors, particularly lymphomas and leukemias, the mechanism appears to be increased metabolism with caloric wastage.
The classic psychiatric illness associated with profound weight loss is anorexia nervosa. Conversion disorders, schizophrenia, and depression may also cause weight loss due to decreased food intake. While organic disease causing both anorexia and depression has to be ruled out, ordinarily the psychiatric nature of the problem will be clear.
One of the earliest manifestations of uremia is anorexia. As a consequence all patients with unexplained weight loss should be given screening renal function tests.
Weight loss is more often a diagnostic problem than weight gain and more often a sign of serious organic illness. If the weight loss is associated with increased food intake, the diagnosis is likely diabetes, thyrotoxicosis, or malabsorption; less frequently, leukemias, lymphomas, or pheochromocytoma cause weight loss in the presence of increased food intake. If food intake is normal or decreased, malignancy, infection, renal disease, psychiatric syndromes, or endocrine deficiency is more common.