A 72-year-old woman undergoes autopsy after death from cardiac failure. Histopathology reveals extensive amyloid deposition in the myocardium, with Congo red staining showing apple-green birefringence. Immunohistochemistry confirms amyloid transthyretin (TTR) deposition. Which is the most common form of transthyretin amyloidosis in this age group?

## Clinical Presentation This elderly patient with cardiac amyloidosis and confirmed TTR deposition represents the most common form of cardiac amyloidosis in the elderly population: wild-type transthyretin amyloidosis (ATTRwt), formerly called senile systemic amyloidosis (SSA). ## Wild-Type Transthyretin Amyloidosis (ATTRwt) **Key Point:** ATTRwt is the most common cause of amyloidosis in the elderly (>60 years) and predominantly affects the heart, presenting with restrictive cardiomyopathy and conduction abnormalities. **High-Yield:** ATTRwt: - Caused by **wild-type (normal) transthyretin** protein that misfolds and deposits with age - Predominantly affects **elderly men** (male predominance ~10:1) - **Cardiac involvement** is the primary manifestation (restrictive cardiomyopathy, atrial fibrillation, conduction blocks) - **Median age at presentation:** 70–80 years - **Prognosis:** Progressive, median survival ~5–10 years from diagnosis ## Comparison of Transthyretin Amyloidosis Types | Type | Genetics | Age of Onset | Primary Organ | Prevalence | Inheritance | |------|----------|--------------|---------------|------------|-------------| | **ATTRwt** | Wild-type TTR (normal sequence) | >60 years | Heart (dominant) | Most common in elderly | Sporadic | | ATTRv | Mutant TTR (>100 mutations known) | 20–50 years | Peripheral nerves (dominant) | Familial, endemic in Portugal/Japan | Autosomal dominant | | ATTRs | Wild-type TTR in setting of chronic disease | Variable | Systemic | Rare | Acquired | | AβM | β2-microglobulin | >5 years on dialysis | Joints, bones, carpal tunnel | Dialysis-associated | Acquired | ## Pathophysiology of ATTRwt 1. **Age-related destabilization** of normal transthyretin tetramer 2. **Dissociation** into monomers and partial unfolding 3. **Misfolding and aggregation** into amyloid fibrils 4. **Deposition** primarily in myocardium, but also in carpal tunnel, spinal canal, and vitreous **Clinical Pearl:** ATTRwt cardiac amyloidosis mimics hypertrophic cardiomyopathy on echocardiography (increased wall thickness, restrictive physiology) but is distinguished by: - Absence of family history (sporadic) - Predominance in elderly males - Presence of carpal tunnel syndrome (often bilateral) - Spinal stenosis from amyloid deposition in ligamentum flavum ## Diagnostic Features - **Congo red staining** with apple-green birefringence under polarized light (as in this case) - **Immunohistochemistry** or **mass spectrometry** confirms TTR type - **Genetic testing:** Normal TTR sequence rules out hereditary form (ATTRv) - **Cardiac imaging:** Echocardiography shows restrictive pattern; cardiac MRI shows late gadolinium enhancement **Mnemonic:** **WILD** — **W**ild-type TTR, **I**n the **L**ate years (elderly), **D**ominant cardiac involvement **High-Yield:** ATTRwt is increasingly recognized as a significant cause of heart failure in the elderly and should be suspected in any patient >60 years with restrictive cardiomyopathy, especially if male.