A 62-year-old woman from Delhi with a 15-year history of rheumatoid arthritis presents with progressive renal dysfunction. Serum creatinine is 2.8 mg/dL, 24-hour urine protein is 4.2 g/day, and urinalysis shows nephrotic-range proteinuria. Renal biopsy shows Congo red-positive deposits in the glomeruli and blood vessel walls with apple-green birefringence. Immunofluorescence microscopy is negative for immunoglobulin and complement deposition. What is the most likely diagnosis?

Question

Accepted Answer

C. AA amyloidosis secondary to chronic rheumatoid arthritis. ## Clinical Context & Pathology Integration

This patient has **secondary amyloidosis (AA amyloidosis)** complicating long-standing rheumatoid arthritis. The Congo red staining with apple-green birefringence confirms amyloid; the negative immunofluorescence excludes immunoglobulin-based disease.

## AA Amyloidosis: Secondary Amyloidosis

**Key Point:** AA amyloidosis is the second most common form of systemic amyloidosis and arises from chronic inflammatory conditions. It is composed of serum amyloid A (SAA), an acute-phase reactant produced during chronic inflammation.

### Pathogenesis
1. Chronic inflammatory state → persistent elevation of SAA
2. Misfolding and aggregation of SAA → amyloid fibril formation
3. Deposition in kidneys (glomeruli, blood vessels), liver, spleen, GI tract

### Clinical Features of AA Amyloidosis
- **Primary organs affected:** Kidneys (most common), liver, spleen
- **Renal presentation:** Nephrotic syndrome, progressive renal failure
- **Immunofluorescence:** Negative (no immunoglobulin/complement) — distinguishes from immune-complex GN
- **Associated conditions:** Chronic infections (TB, osteomyelitis), rheumatoid arthritis, inflammatory bowel disease, Familial Mediterranean Fever (FMF)

### Why This Is AA, Not AL

| Feature | AA Amyloidosis | AL Amyloidosis |
| --- | --- | --- |
| **Underlying disease** | Chronic inflammation (RA, TB, IBD) | Plasma cell dyscrasia (occult or overt) |
| **Organ involvement** | Kidney >> liver, spleen | Heart >> kidney, liver |
| **Cardiac involvement** | Rare | Common (restrictive cardiomyopathy) |
| **Immunofluorescence** | Negative | Negative (but light chains may be detected by mass spec) |
| **Prognosis** | Better if underlying inflammation controlled | Poor without treatment |
| **Treatment** | Control inflammation (DMARDs, biologics) | Chemotherapy, stem cell transplant |

**Clinical Pearl:** The **negative immunofluorescence** is crucial — it excludes immune-complex glomerulonephritis and light chain deposition disease (LCDD), both of which would show positive immunofluorescence.

**High-Yield:** **Chronic inflammation + nephrotic syndrome + Congo red positive + negative immunofluorescence = AA amyloidosis.** The 15-year history of RA is the key clinical clue.

## Mermaid: Amyloidosis Classification

```mermaid
flowchart TD
  A[Systemic Amyloidosis]:::outcome --> B{Underlying Cause?}:::decision
  B -->|Plasma cell dyscrasia| C[AL Amyloidosis]:::outcome
  C --> C1[Light chain: κ or λ]
  B -->|Chronic inflammation| D[AA Amyloidosis]:::outcome
  D --> D1[Serum Amyloid A]
  B -->|Dialysis| E[AβM Amyloidosis]:::outcome
  E --> E1[β2-microglobulin]
  B -->|Genetic: TTR mutation| F[ATTR Amyloidosis]:::outcome
  F --> F1[Hereditary or wild-type]
  D1 --> D2[Organs: kidney >> liver, spleen]
  C1 --> C2[Organs: heart >> kidney, liver]
```

Answer

A. Light chain deposition disease (LCDD)

Answer

B. Membranoproliferative glomerulonephritis secondary to rheumatoid arthritis

Answer

D. AL amyloidosis secondary to occult plasma cell dyscrasia

Explanation

Clinical Context & Pathology Integration

AA Amyloidosis: Secondary Amyloidosis

Pathogenesis

Clinical Features of AA Amyloidosis

Why This Is AA, Not AL

Mermaid: Amyloidosis Classification

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Feature	AA Amyloidosis	AL Amyloidosis
Underlying disease	Chronic inflammation (RA, TB, IBD)	Plasma cell dyscrasia (occult or overt)
Organ involvement	Kidney >> liver, spleen	Heart >> kidney, liver
Cardiac involvement	Rare	Common (restrictive cardiomyopathy)
Immunofluorescence	Negative	Negative (but light chains may be detected by mass spec)
Prognosis	Better if underlying inflammation controlled	Poor without treatment
Treatment	Control inflammation (DMARDs, biologics)	Chemotherapy, stem cell transplant