A 72-year-old man from Bangalore presents with a 2-year history of progressive fatigue, dyspnea, and bilateral carpal tunnel syndrome. He has a history of type 2 diabetes mellitus for 15 years and chronic kidney disease stage 3b (eGFR 35 mL/min/1.73 m²). On examination, he has hepatomegaly and macroglossia. Serum amyloid P scintigraphy shows cardiac and hepatic uptake. Tissue biopsy confirms amyloid with Congo red staining. Genetic testing for TTR mutations is negative. Which is the most likely diagnosis?

Explanation

## Diagnosis: ATTRwt Amyloidosis (Wild-Type Transthyretin Amyloidosis) ### Clinical Presentation Analysis **Key Point:** The combination of advanced age (72 years), cardiac involvement, carpal tunnel syndrome, hepatomegaly, macroglossia, and **negative TTR mutation testing** in a patient without dialysis history is diagnostic of **ATTRwt amyloidosis**. ### Differential Diagnosis of Amyloidosis Types | Feature | ATTRwt | AL | AA | Aβ2M | |---------|---|---|---|---| | **Age at onset** | >60 years (elderly) | 50–70 years | Any age | >50 years (dialysis) | | **Gender** | Male predominance (M:F ~10:1) | M:F ~2:1 | Equal | Equal | | **Genetic mutation** | None (wild-type TTR) | None (plasma cell dyscrasia) | None (secondary to inflammation) | None (dialysis-related) | | **Primary organs** | Heart, PNS, carpal tunnel | Heart, kidneys, nerves | Kidneys, GI, liver | Bone, joints, carpal tunnel | | **Cardiac involvement** | Common, restrictive | Common, restrictive | Rare | Rare | | **Renal involvement** | Rare | Common (nephrotic) | Common (nephrotic) | Rare | | **Hepatomegaly** | Common | Uncommon | Common | Rare | | **Macroglossia** | Occasional | Common | Rare | Rare | | **Carpal tunnel syndrome** | Very common (bilateral) | Uncommon | Rare | Very common | | **Dialysis history** | No | No | No | Yes (mandatory) | | **Chronic inflammation** | No | No | Yes (TB, RA, infection) | No | **High-Yield:** ATTRwt is the most common form of amyloidosis in the elderly, particularly in men >70 years. It was previously called "senile systemic amyloidosis" (SSA). ### Pathophysiology of ATTRwt Amyloidosis 1. **Wild-type transthyretin (TTR)** — normal protein produced by the liver; accumulates with age. 2. **Misfolding and aggregation** → β-pleated sheet amyloid fibrils. 3. **Organ deposition** → restrictive cardiomyopathy (most common cause of death), peripheral neuropathy, carpal tunnel syndrome (often bilateral and recurrent), hepatomegaly, macroglossia. 4. **Cardiac pathology** → thickened ventricular walls, restrictive filling, conduction abnormalities, arrhythmias. **Clinical Pearl:** Bilateral carpal tunnel syndrome in an elderly man is a red flag for ATTRwt amyloidosis — it may precede cardiac symptoms by years. ### Why This Patient Has ATTRwt, Not Other Forms ```mermaid flowchart TD A[Amyloidosis suspected]:::outcome --> B{Age > 60 years?}:::decision B -->|Yes| C{Dialysis history?}:::decision B -->|No| D[Consider AL or AA] C -->|Yes| E[Aβ2M amyloidosis]:::outcome C -->|No| F{TTR mutation present?}:::decision F -->|Yes| G[ATTRm - familial]:::outcome F -->|No| H{Cardiac + carpal tunnel + hepatomegaly?}:::decision H -->|Yes| I[ATTRwt amyloidosis]:::outcome H -->|No| J[Consider AL or AA]:::outcome ``` **Reasoning for this patient:** - **Age 72 (elderly)** → ATTRwt, not AL or AA (which peak in 50–70). - **Bilateral carpal tunnel syndrome** → classic for ATTRwt; rare in AL; absent in AA and Aβ2M. - **Hepatomegaly + macroglossia** → consistent with ATTRwt; hepatomegaly is common in AA but macroglossia is not. - **No dialysis history** → rules out Aβ2M. - **Negative TTR mutation testing** → confirms wild-type (not familial ATTRm). - **Cardiac involvement** → present in ATTRwt; also in AL but AL typically has renal involvement (proteinuria, elevated creatinine) — this patient's renal disease is pre-existing diabetes/CKD, not amyloid-related. ### Diagnostic Confirmation **Mnemonic: WATT** (Wild-type, Age >60, Transthyretin, TTR mutation negative): - **Tissue biopsy** with **Congo red staining** and **apple-green birefringence** under polarized light. - **Immunohistochemistry** or **mass spectrometry** — identifies TTR as the amyloid protein. - **Genetic testing** — **negative for TTR mutations** (distinguishes from ATTRm/familial). - **Serum amyloid P scintigraphy** — shows cardiac and hepatic uptake (as in this patient). - **Cardiac MRI** — late gadolinium enhancement; restrictive physiology on echo. **High-Yield:** ATTRwt has a better prognosis than AL amyloidosis (median survival ~10 years vs. ~1 year for cardiac AL), but cardiac involvement is still the leading cause of death.