What are the differential diagnoses and treatment options for patients presenting with fatigue, weakness, and joint pain, specifically between Iron Deficiency Anemia (IDA), Systemic Lupus Erythematosus (SLE), and hypothyroidism?

Differential Diagnosis: IDA vs SLE vs Hypothyroidism

When evaluating patients with fatigue, weakness, and joint pain, prioritize laboratory testing to distinguish between Iron Deficiency Anemia (IDA), Systemic Lupus Erythematosus (SLE), and hypothyroidism, as these conditions frequently overlap and require distinct management strategies to prevent morbidity.

Key Diagnostic Laboratory Tests

Initial workup must include complete blood count with indices, iron studies (ferritin, transferrin saturation), thyroid function tests (TSH, free T4), and autoimmune markers (ANA, anti-dsDNA, complement levels C3/C4, ESR, CRP). 1, 2

Iron Deficiency Anemia Features

• Microcytic anemia with low hemoglobin and mean cell volume 1
• Low ferritin and transferrin saturation 1
• Specific symptoms: angular stomatitis, glossitis, koilonychia, restless legs syndrome, pagophagia (ice craving), blue sclerae 1
• Screen for celiac disease (present in 3-5% of IDA cases) with serologic testing 1
• Investigate for gastrointestinal blood loss: urinalysis, and in men/postmenopausal women, gastroscopy and colonoscopy 1
• Consider medication history: chronic NSAID use, proton pump inhibitors, blood donation 1

Systemic Lupus Erythematosus Features

• Positive ANA with specific patterns (speckled pattern suggests SLE, Sjögren's, or mixed connective tissue disease) 2
• Positive anti-dsDNA and low complement levels (C3, C4) indicate active lupus 2
• Elevated ESR with normal or mildly elevated CRP is characteristic of SLE (this ESR-CRP discordance is diagnostically significant) 2
• Multi-system involvement: malar rash, photosensitivity, oral ulcers, serositis, renal involvement, neurologic symptoms 2
• Hypothyroidism occurs in 21.5% of SLE patients (significantly higher than general population at 6.9%), often without elevated anti-thyroid antibodies 3, 4
• Joint pain in SLE is typically inflammatory, symmetric, and non-erosive 2

Hypothyroidism Features

• Elevated TSH with low or normal free T4 5
• Symptoms: fatigue, cold intolerance, weight gain, constipation, dry skin, hair loss 5
• Musculoskeletal manifestations: myalgia, arthralgia, joint effusion, and can present as tendinitis (often misdiagnosed as overuse syndrome) 6
• Cardiovascular: bradycardia, diastolic hypertension 5
• Screen for anti-thyroid antibodies (anti-TPO, anti-thyroglobulin) to identify autoimmune thyroiditis 3, 7

Critical Diagnostic Algorithm

Step 1: Evaluate Complete Blood Count and Iron Studies

• If microcytic anemia with low ferritin: Diagnose IDA and investigate underlying cause (GI blood loss, malabsorption, dietary insufficiency) 1
• If normocytic or no anemia: Proceed to autoimmune and thyroid evaluation 1

Step 2: Assess Inflammatory Markers

• Elevated ESR with normal CRP: Strongly suggests SLE or other autoimmune condition over infection or malignancy 2
• Both ESR and CRP elevated: Consider active inflammation from multiple etiologies including infection 1

Step 3: Autoimmune Screening

• Positive ANA at significant titer (≥1:160): Order extractable nuclear antigen panel (anti-dsDNA, anti-Smith, anti-RNP, anti-Ro/SSA, anti-La/SSB) and complement levels 2
• Speckled ANA pattern: Consider Sjögren's syndrome, SLE, mixed connective tissue disease, or undifferentiated connective tissue disease 2
• Negative anti-CCP with positive RF: Less likely rheumatoid arthritis; consider SLE or other autoimmune conditions 2

Step 4: Thyroid Function Assessment

• Check TSH in all patients with fatigue, especially those with SLE (25.3% have thyroid dysfunction) 3, 4
• If TSH elevated: Confirm with free T4 and anti-thyroid antibodies 5, 3
• In SLE patients: Thyroid dysfunction often occurs without elevated anti-thyroid antibodies, so TSH screening is essential regardless of antibody status 3

Common Overlapping Scenarios

IDA + Hypothyroidism

• Both cause fatigue, weakness, and cold intolerance 1, 5, 6
• Hypothyroidism can impair iron absorption and contribute to anemia 1
• Treat both conditions: iron replacement AND levothyroxine 1, 5

SLE + Hypothyroidism

• Hypothyroidism prevalence is 2.93 times higher in SLE patients 4
• Duration of SLE correlates with thyroid dysfunction risk 3
• Screen SLE patients annually for thyroid dysfunction with TSH 3, 4

SLE + IDA

• Chronic inflammation in SLE causes anemia of chronic disease 1
• Concurrent true iron deficiency from GI blood loss (NSAIDs, gastritis) is common 1
• Distinguish by ferritin levels: low in IDA, normal/elevated in anemia of chronic disease 1

Triple Overlap: IDA + SLE + Hypothyroidism

• Autoimmune hypothyroidism can mimic SLE with proteinuria, hematuria, pleural effusion, and arthritis 8
• Evaluate all three simultaneously when clinical picture is unclear 1, 2, 3

Critical Pitfalls to Avoid

• Do not attribute all fatigue to a single diagnosis: Investigate for subclinical disease activity and modifiable factors including sleep disturbance, medication side effects, electrolyte disturbances, vitamin D and B12 deficiency 1
• Do not delay rheumatology referral while awaiting additional autoantibody results in patients with positive ANA and multi-system symptoms 2
• Do not assume normal thyroid function in SLE patients: Screen regularly as thyroid dysfunction often develops during disease course 3, 4
• Do not overlook celiac disease in IDA workup, as it is present in 3-5% of cases and requires specific management 1
• Do not use oral iron alone in severe villous atrophy (celiac disease): IV iron may be necessary 1
• Do not start levothyroxine in patients with adrenal insufficiency without glucocorticoid replacement first, as this can precipitate acute adrenal crisis 5

Treatment Priorities Based on Diagnosis

For IDA

• Oral iron supplementation is first-line unless severe malabsorption, intolerance, or profound anemia 1
• IV iron for severe symptoms, malabsorption (celiac disease with villous atrophy), or oral intolerance 1
• Address underlying cause: treat GI bleeding sources, initiate gluten-free diet for celiac disease 1

For Hypothyroidism

• Levothyroxine replacement with gradual dose titration 5
• Monitor TSH every 6-8 weeks until stable, then annually 5
• In diabetic patients: Monitor glucose closely as levothyroxine may worsen glycemic control 5

For SLE

• Hydroxychloroquine may help with articular symptoms, though evidence for pain/fatigue is limited 1
• Avoid biological agents (rituximab, anakinra) solely for musculoskeletal pain and fatigue, as pivotal trials showed no significant benefit over placebo 1
• Non-pharmacological interventions: Emphasize exercise, psychological support, and sleep hygiene for chronic non-inflammatory pain 1