What is the appropriate workup for a patient with unexplained weight loss?

Workup for Unexplained Weight Loss

Begin with a comprehensive metabolic panel, complete blood count, TSH, HbA1c, and fasting lipid profile as your core laboratory evaluation, then proceed with CT imaging of chest/abdomen/pelvis and age-appropriate cancer screening based on initial findings. 1

Initial Clinical Assessment

Quantify the Weight Loss Severity

• Document percentage of body weight lost: >5% in 3 months or >10% in 6 months is clinically significant and mandates full evaluation 1, 2
• Calculate BMI immediately—BMI <18.5 kg/m² (or <20 kg/m² if age >70 years) indicates severe undernutrition requiring urgent intervention 1, 2
• Measure waist circumference as part of baseline anthropometrics 2

Focused History Elements

• Ask specifically about pain location/characteristics, dysphagia, abdominal pain, changes in bowel habits, GI bleeding, and early satiety—gastrointestinal disorders account for approximately 30% of cases 2, 3
• Screen for constitutional symptoms including fever, night sweats, and changes in functional status 2
• Evaluate dietary intake changes: quantify reduction as 0-25%, 25-60%, or 50-75% of normal in the preceding week 2
• Review all medications systematically—certain antidepressants (mirtazapine, amitriptyline) and antihyperglycemics (glyburide, insulin) cause weight changes 2
• Obtain detailed history of prior weight loss attempts, family history of obesity and comorbidities 4

Physical Examination Priorities

• Inspect for acanthosis nigricans (insulin resistance), hirsutism (PCOS), large neck circumference (sleep apnea), and thin atrophic skin (Cushing's) 4, 2
• Palpate thyroid and assess for tremor, tachycardia, or bradycardia 2
• Examine for lymphadenopathy, hepatosplenomegaly, and abdominal masses 4
• Assess for signs of malignancy: skin lesions, oral lesions, breast masses, anorectal abnormalities 4

Core Laboratory Panel

Order these tests for every patient with unexplained weight loss:

• Comprehensive metabolic panel (electrolytes, renal function, glucose, calcium, liver enzymes, serum albumin) 1, 2
• Complete blood count to screen for anemia, infection, and hematologic malignancy 2
• Thyroid-stimulating hormone (TSH) to screen for hyperthyroidism 1, 2
• Hemoglobin A1c to evaluate for diabetes mellitus—severe hyperglycemia with catabolic features causes weight loss 1, 2
• Fasting lipid profile as part of comprehensive metabolic evaluation 1

Critical Interpretation Pitfall

Do not interpret low serum albumin as confirming malnutrition—it reflects systemic inflammation or acute illness severity, not nutritional status 1. Albumin lacks specificity for nutritional assessment and is highly sensitive to inflammation 1.

Additional Laboratory Tests Based on Clinical Context

• Males with suspected germ cell tumor: AFP and β-hCG 4
• Males with possible prostate cancer: PSA 4
• Females with suspected gynecological primary: CA15-3 and CA125 4
• Suspected GI primary: CEA, CA19-9, and CA72-4 4
• Possible neuroendocrine malignancy: Chromogranin A 4
• Iron studies (ferritin, transferrin saturation) given high prevalence of iron deficiency 1
• Vitamin D levels in patients with limited sun exposure or malabsorption 1
• Vitamin B12 in patients with extensive ileal disease, prior ileal surgery, or vegetarian diet 1

Imaging Strategy

Mandatory Initial Imaging

• CT with IV contrast or MRI of neck, thorax, abdomen, and pelvis for all patients 4
• Chest X-ray for all patients given lung malignancy prevalence 2
• Mammography in all females 4

Specialized Imaging Based on Findings

• MRI brain with contrast if headaches present—urgent neuroimaging is mandatory to exclude intracranial pathology 2
• MRI for suspected head/neck tumors, brain metastases, or pelvic neoplasms 4
• Whole-body FDG-PET/CT is optional but identifies primary tumor in approximately one-third of cases 4

Endoscopic Evaluation

• Gastroscopy and colonoscopy are generally recommended whenever a GI primary is deemed possible 4
• Bronchoscopy may be withheld unless immunohistochemistry or clinical picture suggests lung primary 4

Psychiatric and Nutritional Screening

• Screen for depression, anxiety, eating disorders, and substance abuse—psychiatric disorders account for 16% of cases when organic causes are excluded 2, 3
• Use validated nutritional risk tools: MUST (Malnutrition Universal Screening Tool), NRS-2002 (Nutritional Risk Screening), or SNAQ 3
• Consider screening for disordered eating using validated measures when hyperglycemia and weight loss are unexplained in diabetic patients 2

Cancer Screening Priorities

Malignant diseases account for 22-38% of cases of significant weight loss 1, 2. Ensure adherence to age-appropriate cancer screening guidelines:

• Colonoscopy for colorectal cancer screening 4
• Mammography for breast cancer screening 4
• Low-dose CT for lung cancer screening in appropriate patients 2

When Watchful Waiting Is Appropriate

Watchful waiting is only appropriate if:

• Baseline evaluation is completely normal 2
• Patient remains clinically stable 2
• Close monitoring can be ensured 2

Common Pitfalls to Avoid

• Do not use albumin alone to diagnose malnutrition—it indicates inflammation, not nutritional deficiency 1
• Do not assume "atypical" symptoms rule out serious pathology—the likelihood of finding serious disease is high with significant weight loss 2
• Do not overlook medication review—polypharmacy and specific drugs frequently cause weight loss 1, 2
• Do not delay urgent ophthalmologic examination if headaches present—assess for papilledema indicating increased intracranial pressure 2