A 63-year-old man presents to the emergency department with periorbital swelling. He states that he was gardening, came inside, looked in the mirror, and then noticed his eyelids were swollen. He denies pain, pruritus, or visual disturbances. He states that he was drinking “a lot of water" to prevent dehydration, because it was hot outside this morning. His medical history is significant for rheumatoid arthritis. He takes methotrexate and acetaminophen as needed. The patient’s temperature is 98°F (36.7°C), blood pressure is 168/108 mmHg, and pulse is 75/min. Physical examination is notable for periorbital edema, hepatomegaly, and bilateral 1+ pitting lower extremity edema. Labs and a urinalysis are obtained, as shown below: Leukocyte count: 11,000/mm^3 Hemoglobin: 14 g/dL Serum: Na: 138 mEq/L K+: 4.3 mEq/L Cl-: 104 mEq/L HCO3-: 25 mEq/L Urea nitrogen: 26 mg/dL Creatinine: 1.4 mg/dL Glucose: 85 mg/dL Aspartate aminotransferase (AST, GOT): 15 U/L Alanine aminotransferase (ALT, GPT): 19 U/L Albumin: 2.0 g/dL Urine: Protein: 150 mg/dL Creatinine: 35 mg/dL An abdominal ultrasound reveals an enlarged liver with heterogeneous echogenicity and enlarged kidneys with increased echogenicity in the renal parenchyma. A biopsy of the kidney is obtained. Which of the following biopsy findings is associated with the patient’s most likely diagnosis?

Apple green birefringence with Congo red staining

Glomerular basement membrane splitting

A 55-year-old man comes to the physician because of a 3-day history of decreased urine output, progressively worsening bilateral pedal edema, and fatigue. He has a 4-month history of persistent lower back pain. He has hypercholesterolemia and stable angina pectoris. Current medications include atorvastatin, aspirin, and ibuprofen. His pulse is 80/min, respirations are 16/min, and blood pressure is 150/100 mm Hg. Examination shows periorbital and pedal edema and pallor. There is tenderness of the lumbar spinal vertebrae. Straight leg raise test is negative. The remainder of the examination shows no abnormalities. Laboratory studies show: Hemoglobin 8.9 g/dl Serum Urea nitrogen 20 mg/dl Creatinine 2.4 mg/dl Calcium 11.2 mg/dl Alkaline phosphatase 140 U/L X-ray of the spine shows diffuse osteopenia and multiple lytic lesions. Which of the following is most likely to confirm the diagnosis?

Congo red stain of renal tissue

A 36-year-old man comes to the physician for a 4-week history of swollen legs. He has difficulty putting on socks because of the swelling. Two years ago, he was diagnosed with sleep apnea. He takes no medications. He emigrated from Guatemala with his family when he was a child. He is 171 cm (5 ft 6 in) tall and weighs 115 kg (253 lb); BMI is 39 kg/m2. His pulse is 91/min and blood pressure is 135/82 mm Hg. Examination shows periorbital and bilateral lower extremity edema. Serum Albumin 3.1 g/dL Total cholesterol 312 mg/dL Urine Blood negative Protein +4 RBC 1-2/hpf RBC cast negative Fatty casts numerous A renal biopsy is obtained. Which of the following is most likely to be seen under light microscopy of the patient's renal biopsy specimen?

Segmental sclerosis of the glomeruli

Diffuse thickening of glomerular capillaries

Amyloid deposition in the mesangium

Eosinophilic nodules within the glomeruli

Fibrin crescents within the glomerular space

A 52-year-old man presents with 2 months of diarrhea, abdominal pain, and fatigue. He reports a weight loss of 4 kg (8 lb). He also says his joints have been hurting recently, as well. Past medical history is unremarkable. Review of systems is significant for problems with concentration and memory. Physical examination is unremarkable. A GI endoscopy is performed with a biopsy of the small bowel. Which of the following histologic finding would most likely be seen in this patient?

Non-caseating granulomas in the small intestine

Absence of nerves in the myenteric plexus

Crypt hyperplasia with increased intraepithelial lymphocytes

A 60-year-old woman comes to the physician because of lower back pain, generalized weakness, and weight loss that has occurred over the past 6 weeks. She also says that her urine has appeared foamy recently. Physical examination shows focal midline tenderness of the lumbar spine and conjunctival pallor. Her temperature is 100.5°F (38°C). A photomicrograph of a bone marrow biopsy specimen is shown. Further evaluation of this patient is most likely to show which of the following findings?

Grouped erythrocytes with stacked-coin appearance

Myeloblasts with needle-shaped cytoplasmic inclusions

Erythrocytes with cytoplasmic hemoglobin inclusions

Neutrophils with hypersegmented nuclear lobes

B-lymphocytes with radial cytoplasmic projections

Amyloidosis types for USMLE Step 1: High-Yield Pathology Lessons

Amyloidosis Basics - Misfolded Mayhem

Amyloid: A pathologic, proteinaceous substance deposited extracellularly.
- Structure: Misfolded proteins form a rigid, non-branching fibril with a cross-β-pleated sheet configuration.
- Resistant to normal proteolysis, leading to accumulation.
Pathognomonic Diagnosis:
- Stain: Congo Red.
- Finding: Exhibits classic apple-green birefringence when viewed under polarized light.

Amyloidosis: Congo Red stain with apple-green birefringence

⭐ Despite its name (amyloid ≈ starch-like), the substance is purely proteinaceous, not carbohydrate-based.

Amyloidosis Types - The Protein Perps

Core Defect: Misfolded extracellular proteins aggregate as insoluble beta-pleated sheets. These fibrils deposit in tissues, leading to progressive organ damage and dysfunction.

Type	Precursor Protein	Common Associations & Clinical Clues	Key Organ(s) Involved
AL (Primary)	Ig Light Chain (λ > κ)	Plasma cell dyscrasias (e.g., Multiple Myeloma). Look for monoclonal protein spike.	Kidney (nephrotic syndrome), Heart (restrictive cardiomyopathy), Nerves (neuropathy), Tongue (macroglossia).
AA (Secondary)	Acute-phase reactant SAA	Chronic inflammatory states (RA, IBD, FMF), chronic infections (TB).	Kidney is the most common and major site, often presenting with proteinuria. Also affects liver and spleen.
ATTR	Transthyretin	Senile Systemic: Wild-type TTR in elderly (often >80). Familial: Mutant TTR gene.	Heart is the primary target, leading to restrictive cardiomyopathy and heart failure. Also peripheral nerves.
Aβ	Amyloid-β Precursor Protein	Alzheimer's Disease (forms senile plaques), Down Syndrome (APP gene on Chr 21).	Brain (cerebral cortex). Can also deposit in cerebral vessels (amyloid angiopathy).
Aβ₂M	β₂-microglobulin	Chronic renal failure patients on long-term dialysis (>5 years). Not filtered out by older dialysis membranes.	Musculoskeletal system: Joints (scapulohumeral periarthritis), Bones (cysts), Carpal tunnel syndrome.
%%{init: {'flowchart': {'htmlLabels': true}}}%%
flowchart TD

A["🧪 Precursor Protein
• Soluble protein• Native state"] B["⚠️ Misfolding
• Protein aggregation• Abnormal structures"] C["🧬 Insoluble Fibrils
• Beta-pleated sheets• Fibril formation"] D["🧫 Extracellular
• Amyloid deposition• Tissue buildup"] E["🩺 Organ Failure
• Tissue damage• Organ dysfunction"]

A --> B B --> C C --> D D --> E

style A fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8 style B fill:#FEF8EC, stroke:#FBECCA, stroke-width:1.5px, rx:12, ry:12, color:#854D0E style C fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8 style D fill:#F7F5FD, stroke:#F0EDFA, stroke-width:1.5px, rx:12, ry:12, color:#6B21A8 style E fill:#FDF4F3, stroke:#FCE6E4, stroke-width:1.5px, rx:12, ry:12, color:#B91C1C


> ⭐ **Exam Favorite:** Regardless of the biochemical type, all amyloid deposits stain with Congo red, producing a characteristic apple-green birefringence when viewed under polarized light. This is the gold standard for diagnosis.

## Clinical Picture & Dx - Systemic Sabotage

*   **Systemic Involvement** - a multi-organ assault:
    -   **Cardiac:** Restrictive cardiomyopathy (diastolic dysfunction) → HFpEF. Classic finding: ↓ voltage ECG with ↑ ventricular wall thickness on echo.
    -   **Renal:** Nephrotic syndrome is the hallmark. Massive proteinuria, edema.
    -   **GI:** Macroglossia (enlarged, scalloped tongue), malabsorption, hepatosplenomegaly.
    -   **Neurologic:** Peripheral & autonomic neuropathy (e.g., carpal tunnel, orthostatic hypotension).

> ⭐ Low voltage on ECG despite a thickened myocardium on echocardiogram is a pathognomonic finding for cardiac amyloidosis.

*   **Definitive Diagnosis:**

```mermaid
%%{init: {'flowchart': {'htmlLabels': true}}}%%
flowchart TD

Start["<b>📋 Clinical Suspicion</b><br><span style='display:block; text-align:left; color:#555'>• Assess symptoms</span><span style='display:block; text-align:left; color:#555'>• Organ dysfunction</span>"]
Biopsy["<b>🔬 Biopsy</b><br><span style='display:block; text-align:left; color:#555'>• Tissue sampling</span><span style='display:block; text-align:left; color:#555'>• Pathological exam</span>"]
Site["<b>📍 Biopsy Site</b><br><span style='display:block; text-align:left; color:#555'>• Abdominal fat pad</span><span style='display:block; text-align:left; color:#555'>• Rectal submucosa</span>"]
Congo["<b>🔬 Congo Red Stain</b><br><span style='display:block; text-align:left; color:#555'>• Amyloid affinity</span><span style='display:block; text-align:left; color:#555'>• Binding pattern</span>"]
Apple["<b>🍏 Birefringence</b><br><span style='display:block; text-align:left; color:#555'>• Apple-green color</span><span style='display:block; text-align:left; color:#555'>• Polarized light</span>"]
MassSpec["<b>🔬 Mass Spectrometry</b><br><span style='display:block; text-align:left; color:#555'>• Amyloid typing</span><span style='display:block; text-align:left; color:#555'>• Protein analysis</span>"]

Start --> Biopsy
Biopsy --> Site
Site -->|Staining| Congo
Congo -->|Polarized Light| Apple
Apple -->|For Typing| MassSpec

style Start fill:#FEF8EC, stroke:#FBECCA, stroke-width:1.5px, rx:12, ry:12, color:#854D0E
style Biopsy fill:#FFF7ED, stroke:#FFEED5, stroke-width:1.5px, rx:12, ry:12, color:#C2410C
style Site fill:#FFF7ED, stroke:#FFEED5, stroke-width:1.5px, rx:12, ry:12, color:#C2410C
style Congo fill:#FFF7ED, stroke:#FFEED5, stroke-width:1.5px, rx:12, ry:12, color:#C2410C
style Apple fill:#F6F5F5, stroke:#E7E6E6, stroke-width:1.5px, rx:12, ry:12, color:#525252
style MassSpec fill:#FFF7ED, stroke:#FFEED5, stroke-width:1.5px, rx:12, ry:12, color:#C2410C

Macroglossia with tooth indentations in amyloidosis

High‑Yield Points - ⚡ Biggest Takeaways

Primary (AL) amyloidosis is caused by monoclonal plasma cells depositing Ig light chains.

Secondary (AA) amyloidosis complicates chronic inflammation (e.g., RA), depositing serum amyloid A (SAA).

ATTR amyloidosis involves transthyretin deposits, causing restrictive cardiomyopathy, especially in the elderly.

Dialysis-related amyloidosis results from β2-microglobulin accumulation, often presenting with carpal tunnel syndrome.

Alzheimer's disease is characterized by cerebral Aβ amyloid plaques.

The pathognomonic finding for all types is Congo red staining with apple-green birefringence.

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