What is the differential diagnosis for a patient presenting with anasarca, severe hypoproteinemia (low protein/cr 333), low prealbumin, normal albumin, normal total protein, mild anemia (hemoglobin 10), normal haptoglobin, normal lactate dehydrogenase (LDH), normal echocardiogram, normal computed tomography (CT) abdomen, no hematuria, normal creatinine, normal liver function tests (LFTs), and low complement levels (C3 and C4)?

Differential Diagnosis: Anasarca with Low Complements and Severe Proteinuria

The most likely diagnosis is systemic lupus erythematosus (SLE) with lupus nephritis, given the combination of anasarca, severe proteinuria (protein/creatinine ratio 333), low C3 and C4, and normal renal function—this patient requires immediate serologic testing for anti-dsDNA antibodies, anti-Sm antibodies, and ANA, followed by renal biopsy if SLE is confirmed. 1

Primary Diagnostic Consideration: Lupus Nephritis

The constellation of low C3 and C4 with severe proteinuria strongly suggests active lupus nephritis, particularly Class V (membranous) given the preserved renal function and absence of hematuria. 1, 2

Key Supporting Features:

• Low complement levels (C3 and C4) are characteristic of active SLE and should be monitored serially every 3 months in confirmed cases 1, 2
• Severe proteinuria with normal creatinine is typical of Class V lupus nephritis, which presents with nephrotic-range proteinuria but preserved GFR 3
• Anasarca with low prealbumin but normal albumin creates a diagnostic puzzle—the normal serum albumin despite severe edema suggests either laboratory error or protein-losing enteropathy as an additional mechanism 4, 5, 6
• Mild anemia (hemoglobin 10) is a predictor of long-term outcome in lupus nephritis and reflects chronic disease activity 1

Immediate Diagnostic Workup:

• Anti-dsDNA antibodies and anti-Sm antibodies should be measured immediately, as these are highly specific for SLE 1, 6
• Complete ANA panel including anti-nuclear antibody titer 6
• Anti-phospholipid antibodies should be checked given the risk of thrombotic complications 1
• Renal biopsy is indicated to confirm lupus nephritis class and guide immunosuppressive therapy, particularly since proteinuria exceeds 50 mg/mmol 1

Alternative Diagnosis: SLE with Protein-Losing Enteropathy

If serum albumin measurement is accurate, consider protein-losing enteropathy as a rare but documented manifestation of SLE, which can present with anasarca and low C3/C4. 4, 5, 6

Distinguishing Features:

• Normal albumin with low prealbumin is unusual—verify albumin measurement and consider checking total serum protein 1
• Protein-losing enteropathy in SLE presents with severe hypoalbuminemia (often <2 g/dL), anasarca, and gastrointestinal protein loss without active nephritis 4, 5, 6
• 99mTc-labeled albumin scintigraphy can confirm gastrointestinal protein loss if suspected 6
• Intestinal venulitis with C3 deposition has been documented on full-thickness jejunal biopsy in SLE patients with protein-losing enteropathy 5

Clinical Pitfall:

The combination of severe proteinuria (protein/cr 333) with normal albumin is internally inconsistent—either the albumin is falsely normal, or there are two simultaneous protein-wasting processes (renal + gastrointestinal). 4, 6

Complement Deficiency Syndromes (Less Likely)

Primary complement deficiencies (C4A or C4B deficiency) predispose to SLE-like syndromes but would not explain the severe proteinuria and anasarca without underlying lupus nephritis. 1, 7

Key Considerations:

• C4 deficiency is a strong risk factor for developing lupus erythematosus, but 50% of patients with partial C4 deficiency have normal C3, C4, and CH50 levels 7
• CH50 and AH50 testing should be performed to differentiate primary complement deficiency from complement consumption 1
• Low C3 and C4 together suggests complement consumption (active SLE) rather than isolated complement deficiency 1, 2
• Normal C1q level would help exclude acquired C1 inhibitor deficiency, which presents with low C4 but typically low C1q 1

Acquired C1 Inhibitor Deficiency (Unlikely)

Acquired C1 inhibitor deficiency typically presents with angioedema rather than anasarca and would show low C1q levels, which should be checked to exclude this diagnosis. 1

Distinguishing Features:

• Low C4 with normal C1q favors lupus over acquired C1 inhibitor deficiency 1
• Absence of angioedema episodes makes hereditary or acquired angioedema unlikely 1

Recommended Diagnostic Algorithm

1. Verify laboratory values: Repeat albumin, total protein, and complement levels to confirm accuracy 1
2. Complete SLE serologies: ANA, anti-dsDNA, anti-Sm, anti-phospholipid antibodies 1, 6
3. Assess for complement consumption vs. deficiency: Order CH50, and consider C1q level 1
4. Renal biopsy: Essential for confirming lupus nephritis class and guiding immunosuppression 1
5. If albumin truly normal: Consider 99mTc-albumin scan to evaluate for protein-losing enteropathy 6

Treatment Implications

If lupus nephritis is confirmed, initiate immunosuppression with mycophenolate mofetil (MMF) or cyclophosphamide plus glucocorticoids, with ACE inhibitors for proteinuria control. 1

• Initial therapy for Class III/IV lupus nephritis: MMF (target 3g/day) or IV cyclophosphamide with high-dose glucocorticoids 1
• Class V lupus nephritis: May respond to MMF or calcineurin inhibitors 1
• ACE inhibitors or ARBs are indicated for proteinuria >50 mg/mmol 1
• Hydroxychloroquine should be added to reduce renal flares and cardiovascular damage 1
• If protein-losing enteropathy confirmed: Low-dose corticosteroids (prednisolone 40mg/day) with azathioprine (100mg/day) have shown efficacy 4, 6