Involuntary weight loss is a common problem seen in a general medical practice. It usually involves serious underlying medical or psychiatric problems; therefore, a thorough evaluation to determine its cause is mandatory. The causes of involuntary weight loss are myriad and include malignancies, vasculitis, malabsorption, endocrinopathies, chronic medical illness, smoldering infections, advanced cardiopulmonary disease, drugs, alcoholism, and psychiatric disorders. In contrast, involuntary weight loss without underlying disease frequently occurs in the geriatric population. The broad range of the differential diagnoses necessitates an organized workup to ensure accurate and timely diagnosis, avoid oversights, and minimize patient inconvenience. We propose a 3-step approach to advance these goals.

Clinically significant weight loss can be defined as a loss of 10 lb (4.5 kg) or more of usual body weight in a period of 6 months or less.¹ Significant weight loss usually involves serious underlying medical or psychiatric problems, so a thorough evaluation to determine its cause is required when the loss exceeds 5% of the patient’s usual body weight. Unintentional weight loss occurs in up to 10% of adult outpatients,² 13% of elderly outpatients,³ and 50% to 65% of nursing home patients.⁴ 

Involuntary weight loss of more than 10% of usual body weight represents protein-energy malnutrition¹ and can lead to decreased humoral immunity and frank organ dysfunction.^4,5 Involuntary weight loss in patients of all ages is associated with increased morbidity, including impaired functioning, poor wound healing, greater number and severity of infections, and an increased risk of mortality that can range from 7% to as high as 31%.^6,7 

Causes and Classification
The spectrum of disorders that cause involuntary weight loss is listed in Table 1. These causes can broadly be grouped into organic, psychiatric (including drug or alcohol abuse), and functional/idiopathic. It is also useful to categorize the causes by their effect on appetite. Endocrine and malabsorption syndromes typically present with a preserved or increased appetite, whereas malignancy, chronic medical illness, advanced cardiopulmonary diseases, psychiatric conditions, alcoholism, and drug abuse present with varying degrees of anorexia. Idiopathic and/or functional involuntary weight loss accounts for up to one fourth of all such cases.⁸

Organic causes
Malignancies. Cancer leads the list of organic causes of involuntary weight loss, accounting for 24% to 38% of all cases.^9,10 Involuntary weight loss with anorexia may be the only signs of a malignancy. Cancer-associated weight loss is not solely related to tumor burden. Patients have also been noted to have a systemic inflammatory response associated with increased energy expenditure mediated by the cytokines tumor necrosis factor-alpha and interleukin-6.¹¹ 

Virtually any visceral cancer can present with involuntary weight loss. Gastrointestinal (GI) malignancies may directly contribute to weight loss by their impact on peristalsis and absorption. In one study, more than 50% of malignant disorders diagnosed in patients with involuntary weight loss was associated with the GI system.⁹ 

Gastrointestinal. Nonmalignant GI disorders are the second most common organic cause (10%) of involuntary weight loss.¹⁰ Anorexia with weight loss occurs in many GI disorders, leading to telltale symptoms, such as dysphagia, early satiety, nausea, vomiting, abdominal pain, or diarrhea. Diarrhea and unexplained weight loss associated with a normal or increased appetite suggests the presence of a malabsorption syndrome.

Endocrine. In about 8% of cases, involuntary weight loss is due to an endocrinologic condition.¹⁰ Hyperthyroidism and uncontrolled diabetes mellitus often come to medical attention because of unexplained weight loss, even though these conditions are characterized by normal or increased appetite. In hyperthyroidism, the weight loss is due to increased energy expenditure and GI motility. In uncontrolled diabetes mellitus, the weight loss is caused by an osmotic diuresis and failure to transport glucose into the intracellular space.

Less common endocrinopathies associated with unexplained weight loss include pheochromocytoma, panhypopituitarism, adrenal insufficiency, and hyperparathyroidism.^12,13

General illnesses. Advanced disease of nearly all organ systems may result in weight loss.¹⁴ Cardiac cachexia in advanced congestive heart failure and respiratory cachexia in advanced chronic obstructive pulmonary disease are well-recognized examples of organ failure resulting in weight loss.

Weight loss and muscle wasting are common features of HIV infection. Vasculitis, a particularly difficult systemic syndrome to diagnose, can also present with malaise, weakness, and weight loss.

Psychiatric causes
Endogenous. Psychiatric disorders are responsible for 11% to 33% of cases.^9,15 Involuntary weight loss is a cardinal symptom of major depression and one of its most objective diagnostic criteria. Depression is responsible for unintentional weight loss in about 19% of outpatients¹⁰ and in 36% of nursing home residents.¹⁶

Other psychiatric disorders associated with weight loss and anorexia include bipolar disorder, Munchausen syndrome, and delusional or paranoid disorders. Withdrawal from long-term therapy with neuroleptic medications can also lead to involuntary weight loss.¹⁷ 

Depression and dementia are common causes of involuntary weight loss in the geriatric population.^16,18 A new study shows that rapid weight loss in patients aged 65 to 95 years often precedes the diagnosis of Alzheimer’s disease.¹⁹ Neuropsychiatric abnormalities may also indicate deficiencies of vitamins, such as folate and vitamins B₁₂ and B₁, concomitant with weight loss or caused by weight loss.^20,21

Exogenous. Chronic drug use is an all-too-common symptom of a psychiatric disorder. Addiction to a variety of drugs can cause decreased appetite and weight loss. Heavy smokers tend to be thin; tobacco cessation is associated with weight gain. Amphetamines and cocaine are well-recognized anorectics, and opiates suppress the appetite center.

Drugs used to treat psychiatric problems can also lead to anorexia and weight loss. For example, methylphenidate HCl (Concerta, Methylin, Ritalin), which is used to treat attention-deficit/hyperactivity disorder has amphetaminelike properties. Selective serotonin reuptake inhibitors have been associated with weight gain as well as weight loss. Nonpsychiatric medications associated with weight loss include digoxin (Digitek, Lanoxicaps, Lanoxin), metformin HCl (Fortamet, Glucophage), and levodopa (Larodopa).

Functional/idiopathic
Functional. Not all involuntary weight loss can be attributed to an organic or psychiatric disease. Significant weight loss is a common physiologic manifestation of the aging process that is seen in the 8th, 9th, and 10th decades of life. In this setting, the appetite is usually preserved.

In contrast, in younger persons, abrupt increases in physical activity over a long period of time may also lead to involuntary weight loss.^4,16 

Idiopathic. Idiopathic weight loss accounts for about one fourth of all cases.⁸ Because up to two thirds of patients with involuntary weight loss have serious underlying organic or psychiatric pathology,²² it is only with great trepidation that the label “idiopathic condition” should be assigned by the prudent clinician.

Thus, a well-designed and thorough workup to identify the basis for involuntary weight loss will not always uncover a serious medical or psychiatric illness. In addition, no conscientious physician wants to miss diagnosing a serious condition. At the same time, it is important to recognize that involuntary weight loss in 1 in 4 patients will be idiopathic or functional, and therein resides the dilemma.

Patient Evaluation: The 3-Step Approach
A systematic approach to involuntary weight loss is necessary, to avoid unwieldy workups that can create clinical confusion, and at great expense and inconvenience to the patient. To this end, we propose the following 3-step approach to the diagnosis of involuntary weight loss, as outlined in Table 2.

Step 1: Initial assessment
As a result of the breadth of the differential diagnoses for involuntary weight loss, thorough history taking and physical examination are essential. The “big 3” causes of involuntary weight loss are malignancies, nonmalignant GI disorders, and psychiatric (excluding idiopathic) illness. Collectively, these account for more than two thirds of all cases.^10,22 Accordingly, key topics to cover in the history include the American Cancer Society’s 7 warning signs of cancer:
• Change in bowel or bladder habits
• A sore that does not heal
• Unusual bleeding or discharge
• Lump in the breast or other part of the body
• Indigestion or difficulty swallowing
• Obvious changes in a wart or mole
• Persistent coughing or hoarseness.

GI and psychologic signs and symptoms should be meticulously reviewed. Special attention should be paid to appetite, which, when increased, suggests an endocrine cause.

Other important components to investigate are:
• Alcohol/drug use
• High-risk behaviors (eg, sexual, drug, or alcohol abuse)
• Constitutional symptoms
• Changes in physical activity
• Fever/chills
• Prosthetic devices
• Valvular heart disease
• Travel history
• Recent illnesses
• Other medical conditions.

In the physical examination, special attention should be paid to dentition; the oropharynx; the entire thoracoabdominal region, including the breast and rectum; and a diligent search for lumps, bumps, masses, and lymphadenopathy.

Initial laboratory testing should include a complete blood cell (CBC) count, erythrocyte sedimentation rate, thyroid-stimulating hormone measurement, comprehensive metabolic profile, iron studies, fecal occult blood testing (FOBT), and urinalysis.

Other tests may be appropriate, depending on the circumstances and patient demographics; these include prostate-specific antigen, purified protein derivative, and HIV tests; blood cultures; tests for rheumatoid arthritis, antinuclear antibody, parathyroid hormone, antigliadin antibodies, amylase, lipase, and hemoglobin A_1c; and a urine drug screen.

Step 2: Imaging
The purpose of imaging is to search for solid pathology, including lymphadenopathy, anywhere from the neck to the pelvis. A contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis is recommended because of its universal availability. Combination CT/positron-emission tomography scans are superior for the detection of occult cancers, but they are more expensive and not as universally available.

All women with involuntary weight loss should undergo mammography. In cases where the history and/or physical examination findings raise concerns for endovascular infection, an echocardiogram is indicated.

Patients with prosthetic devices should undergo special imaging procedures to suit the type and location of the device. Nuclear bone scanning is indicated if osteomyelitis is suspected.

Step 3: GI endoscopy
Not all patients with involuntary weight loss require GI endoscopy. If the diagnosis of involuntary weight loss is apparent after completing steps 1 and 2, and if the CBC count, iron studies, and FOBT are all normal, it is acceptable to withhold this more invasive step. However, if the diagnosis remains obscure after the first 2 steps, GI endoscopy is recommended.

Indications for panendoscopy include upper or lower GI symptoms, microcytic anemia, low serum iron or total iron saturation, and a positive FOBT.

Conclusion
The 3-step approach to the diagnosis of patients with involuntary weight loss will help identify any potential organic cause expediently. The elements of the first 2 steps may be done during the initial visit. Thus, on the first follow-up visit, the diagnosis may be evident. If not, it may be time to proceed with the more invasive and expensive endoscopic examinations. Remember that roughly one fourth of all cases of involuntary weight loss are functional or idiopathic, but that label should not be applied by assumption.

Self-assessment test
1. Weight loss can be caused with chronic use of all the following drugs, except:
A. Amphetamines
B. Digoxin
C. Metformin HCl
D. Neuroleptic medications

2. All the following conditions are associated with decreased appetite, except:
A. Hypercalcemia
B. Alcoholism
C. Lymphoma
D. Advanced renal disease

3. Which of the following conditions is NOT among the 3 most common causes of involuntary weight loss?
A. Endocrinologic conditions
B. Malignancies
C. Nonmalignant GI disorders
D. Psychiatric conditions

4. Core laboratory tests in the evaluation of unintentional weight loss include all the following, except:
A. Erythrocyte sedimentation rate
B. Comprehensive metabolic profile
C. Parathyroid hormone measurement
D. FOBT

5. Which statement about imaging with unintended weight loss is
NOT true?
A. All patients should undergo contrast-enhanced CT scanning from neck to pelvis
B. Mammography is indicated in all women
C. All patients should undergo GI endoscopy
D. Echocardiography is required if an endovascular infection is suspected

(Answers at end of reference list)

References
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3. Sahyoun NR, Serdula MK, Galuska DA, et al. The epidemiology of recent involuntary weight loss in the United States population. J Nutr Health Aging. 2004; 8:510-517.

4. Marton KI, Sox HC Jr, Krupp JR. Involuntary weight loss: diagnostic and prognostic significance. Ann Intern Med. 1981; 95:568-574.

5. Ritz BW, Gardner EM. Malnutrition and energy restriction differentially affect viral immunity. J Nutr. 2006; 136: 1141-1144.

6. Newman AB, Yanez D, Harris T, et al. Weight change in old age and its association with mortality. J Am Geriatr Soc. 2001; 49:1309-1318.

7. Gregg EW, Gerzoff RB, Thompson TJ, et al. Intentional weight loss and death in overweight and obese US adults 35 years of age and older. Ann Intern Med. 2003; 138: 383-389.

8. Thompson MP, Morris LK. Unexplained weight loss in the ambulatory elderly. J Am Geriatr Soc. 1991; 39: 497-500.

9. Lankisch P, Gerzmann M, Gerzmann JF, et al. Unintentional weight loss: diagnosis and prognosis. The first prospective follow-up study from a secondary referral centre. J Intern Med. 2001; 249:41-46.

10. Hernandez JL, Riancho JA, Matorras P, et al. Clinical evaluation for cancer in patients with involuntary weight loss without specific symptoms. Am J Med. 2003; 114:631-637.

11. Staal-van den Brekel AJ, Dentener MA, Schols AM, et al. Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol. 1995; 13:2600-2605.

12. Reife CM. Involuntary weight loss. Med Clin North Am. 1995; 79: 299-313.

13. Bouras EP, Lange SM, Scolapio JS. Rational approach to patients with unintentional weight loss. Mayo Clin Proc. 2001; 76:923-929.

14. Pirlich M, Norman K, Lochs H, et al. Role of intestinal function in cachexia. Curr Opin Clin Nutr Metab Care. 2006; 9:603-606.

15. Bilbao-Garray J, Barba R, Losa-Garcia JE, et al. Assessing clinical probability of organic disease in patients with involuntary weight loss: a simple score. Eur J Intern Med. 2002; 13;240-245.

16. Morley JE, Kraenzle D. Causes of weight loss in a community nursing home. J Am Geriatr Soc. 1994; 42: 583-585.

17. Zuddas A, Di Martino A, Muglia P, et al. Long-term risperidone for pervasive developmental disorder: efficacy, tolerability, and discontinuation. J Child Adolesc Psychopharmacol. 2000; 10:79-90.

18. Guerin O, Andrieu S, Schneider SM, et al. Different modes of weight loss in Alzheimer disease: a prospective study of 395 patients. Am J Clin Nutr. 2005; 82:435-441.

19. Johnson DK, Wilkins CH, Morris JC. Accelerated weight loss may precede diagnosis in Alzheimer disease. Arch Neurol. 2006; 63: 1312-1317.

20. McCaddon A. Homocysteine and cognition—a historical perspective. J Alzheimers Dis. 2006; 9: 361-380.

21. Winston AP, Jamieson CP, Madira W, et al. Prevalence of thiamin deficiency in anorexia nervosa. Int J Eat Disord. 2000; 28: 451-454.

22. Hernandez JL, Matorras P, Riancho JA, et al. Involuntary weight loss without specific symptoms: a clinical prediction score for malignant neoplasm. Q J Med. 2003; 96:649-655.

Answers: 1. D; 2. A; 3. A; 4. C; 5. C.