What is the approach to assessing weight loss of 6 months duration, including definition, differential diagnosis, history, physical examination, investigations, empiric treatment, and indications for referral?

Approach to Assessment of Unintentional Weight Loss (6 Months Duration)

Definition

Clinically significant unintentional weight loss is defined as loss of ≥5% of body weight over 6 months without deliberate effort to lose weight 1, 2. This threshold warrants thorough investigation due to associations with increased morbidity and mortality 3.

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Differential Diagnosis

Most Common Causes (in order of frequency):

• Malignancy (22% of cases with organic causes) - particularly gastrointestinal, lung, hematologic 1, 4
• Non-malignant gastrointestinal disorders - malabsorption syndromes, peptic ulcer disease, inflammatory bowel disease, chronic pancreatitis 4, 3
• Psychiatric disorders - depression (most common), anxiety, eating disorders 4, 3
• Endocrine disorders - hyperthyroidism, diabetes mellitus, adrenal insufficiency 5, 3
• Chronic infections - tuberculosis, HIV, endocarditis, chronic fungal infections 5, 3
• Cardiac disease - congestive heart failure, ischemic heart disease 3
• Medications - digoxin, metformin, SSRIs, NSAIDs, chemotherapy agents 5
• Social factors (especially in elderly) - poverty, isolation, inability to shop/cook, poor dentition 2, 5
• Idiopathic - no cause identified in approximately 25% of cases despite extensive workup 1, 3

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History

Character of Weight Loss:

• Quantify exact amount lost - ask patient to provide specific numbers in kg or pounds 5
• Timeline - rate of loss (rapid vs gradual) 5
• Intentionality - confirm truly unintentional, not due to dieting or lifestyle changes 5
• Appetite changes - preserved appetite suggests malabsorption or hyperthyroidism; decreased appetite suggests malignancy or depression 5, 3

Red Flags (Strongly Suggest Organic Disease):

• Constitutional symptoms - fever, night sweats, fatigue 5
• Gastrointestinal symptoms - dysphagia, odynophagia, persistent nausea/vomiting, change in bowel habits, melena, hematochezia 5, 4
• Respiratory symptoms - chronic cough, hemoptysis, dyspnea 5
• Neurologic symptoms - headache, focal deficits, cognitive changes 5
• Lymphadenopathy or palpable masses 5
• Age >65 years - higher likelihood of malignancy 4

Risk Factors to Elicit:

• Smoking history - lung cancer, COPD 5
• Alcohol use - cirrhosis, pancreatitis, malnutrition 5, 3
• Medication review - complete list including over-the-counter and supplements 5
• Social history - living situation, financial resources, ability to obtain/prepare food 2, 5
• Psychiatric history - depression screening (PHQ-9), anxiety 2, 4
• Family history - malignancy, inflammatory bowel disease, celiac disease 5
• Travel history - tuberculosis, parasitic infections 5
• Sexual history - HIV risk factors 5

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Physical Examination (Focused)

Vital Signs:

• Temperature - fever suggests infection or malignancy 5
• Heart rate - tachycardia suggests hyperthyroidism or cardiac disease 5
• Blood pressure - orthostatic hypotension suggests volume depletion or adrenal insufficiency 5

General Appearance:

• Cachexia vs sarcopenia - muscle wasting pattern 5
• Temporal wasting - suggests significant protein-energy malnutrition 5

Specific Examination Findings:

• Oral cavity - dentition, oral thrush, masses 2, 5
• Thyroid - goiter, nodules 5
• Lymph nodes - cervical, supraclavicular, axillary, inguinal adenopathy 5, 4
• Cardiac - murmurs, signs of heart failure (JVD, S3 gallop, peripheral edema) 5
• Pulmonary - decreased breath sounds, crackles, wheezing 5
• Abdominal - masses, hepatosplenomegaly, ascites, tenderness 5, 4
• Rectal - masses, occult blood 5, 4
• Skin - rashes, hyperpigmentation (Addison's), jaundice 5
• Neurologic - focal deficits, cognitive impairment 5

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Investigations (Baseline Evaluation)

Initial Laboratory Tests:

• Complete blood count - anemia (malignancy, GI bleeding), leukocytosis/leukopenia (infection, hematologic malignancy) 1, 5
• Comprehensive metabolic panel - electrolytes, renal function, liver function tests, albumin 1, 5
• C-reactive protein - elevated suggests inflammation, infection, or malignancy 1
• Thyroid-stimulating hormone - hyperthyroidism 5, 3
• Hemoglobin A1c or fasting glucose - uncontrolled diabetes 5
• Urinalysis - proteinuria, hematuria 5
• Fecal occult blood test - GI malignancy or bleeding 5

Initial Imaging:

• Chest X-ray - lung malignancy, tuberculosis, heart failure 1, 5
• Abdominal ultrasound - hepatobiliary disease, pancreatic masses, lymphadenopathy 1, 5

Expected Findings:

• If malignancy present: baseline evaluation is abnormal in 100% of cases 1
• If non-malignant organic disease: baseline evaluation is abnormal in 94% of cases 1
• If no organic cause: baseline evaluation is normal in 52% of cases 1

Second-Tier Testing (If Initial Workup Negative):

• HIV testing - if risk factors present 5, 4
• Tuberculin skin test or interferon-gamma release assay - if risk factors or endemic area 5
• Tissue transglutaminase antibodies - celiac disease 5
• Cortisol level - adrenal insufficiency 5
• Upper endoscopy - if upper GI symptoms 4
• Colonoscopy - if age-appropriate screening not done or lower GI symptoms 4
• CT chest/abdomen/pelvis - if high suspicion for occult malignancy 4

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Empiric Treatment

No empiric treatment should be initiated until diagnostic evaluation is complete, as treating symptoms may mask underlying serious pathology 5, 3.

Once Diagnosis Established:

• Treat underlying cause first - this is the primary intervention 2, 3
• Nutritional support - dietitian referral for caloric supplementation if indicated 2
• Address social barriers - meal delivery services, social work consultation for elderly or isolated patients 2
• Psychiatric treatment - antidepressants for depression, though note these may initially worsen weight loss 2, 3

If No Cause Found After Complete Workup:

• Watchful waiting is preferable to undirected invasive testing 1, 2
• Close follow-up every 3-6 months - repeat history, physical examination, and basic labs 1, 3
• Nutritional support - ensure adequate caloric intake 2

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Indications to Refer

Immediate Referral:

• Suspected malignancy - oncology or appropriate surgical subspecialty 4
• Severe malnutrition - albumin <2.5 g/dL, BMI <16 kg/m² - consider hospitalization 2
• Acute life-threatening conditions - GI bleeding, bowel obstruction 5

Subspecialty Referral:

• Gastroenterology - for endoscopy if GI symptoms or occult blood positive 4
• Endocrinology - if thyroid or adrenal disorders suspected 5
• Psychiatry - if severe depression or eating disorder 4
• Geriatrics - for elderly patients with multifactorial causes 2
• Nutrition/Dietitian - all patients with significant weight loss for nutritional assessment and support 2

Referral if No Diagnosis After 6 Months:

• Consider tertiary care center - for complex cases without diagnosis despite thorough evaluation 3

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Critical Pitfalls

Diagnostic Pitfalls:

• Failing to quantify weight loss objectively - always obtain documented weights, not just patient report 5
• Pursuing extensive testing when baseline evaluation is completely normal - this yields minimal additional diagnoses and watchful waiting is more appropriate 1
• Missing medication-induced weight loss - always review complete medication list including over-the-counter drugs 5
• Overlooking social and psychiatric causes - these are common, especially in elderly, and often missed 2, 4
• Assuming weight loss in elderly is "normal aging" - significant weight loss always warrants investigation regardless of age 2, 3
• Not recognizing that 25% of cases remain idiopathic - avoid over-testing when initial comprehensive evaluation is negative 1, 3

Management Pitfalls:

• Initiating empiric treatment before establishing diagnosis - may mask serious underlying pathology 5, 3
• Inadequate follow-up - patients with idiopathic weight loss require close monitoring as diagnoses may emerge over time 1, 3
• Focusing solely on weight gain rather than treating underlying cause - the primary goal is identifying and treating the etiology 2, 3
• Neglecting nutritional support - even while pursuing diagnosis, patients need adequate nutrition to prevent further deterioration 2
• Missing depression - this is a leading cause but often overlooked; formal screening should be performed 2, 4