Amyloidosis: From Misfolded Proteins to Multi-Organ Failure

A Contemporary Review for the Practicing Internist

Dr Neeraj Manikath , claude.ai

Abstract

Amyloidosis represents a group of protein misfolding disorders characterized by extracellular deposition of insoluble fibrils, leading to progressive organ dysfunction and, if untreated, death. Despite significant advances in diagnostic techniques and therapeutics, amyloidosis remains underdiagnosed due to its protean clinical manifestations that frequently mimic more common diseases. This review provides a practical approach to recognizing, diagnosing, and managing the two most clinically significant subtypes—AL (light-chain) and ATTR (transthyretin) amyloidosis—with emphasis on pearls for early detection, non-invasive diagnostic algorithms, and emerging targeted therapies that have transformed prognosis in recent years.

Introduction: The Great Masquerader

Amyloidosis is not a single disease but rather a spectrum of disorders united by a common pathologic mechanism: the misfolding of normally soluble proteins into insoluble, β-pleated sheet fibrils that deposit in tissues, disrupting architecture and function¹. Over 30 different precursor proteins can form amyloid, but AL and ATTR amyloidosis account for the vast majority of cases encountered in clinical practice².

The cardinal challenge facing internists is that amyloidosis rarely announces itself. Instead, it masquerades as heart failure with preserved ejection fraction (HFpEF), nephrotic syndrome, peripheral neuropathy, or unexplained macroglossia. The median delay from symptom onset to diagnosis often exceeds two years³, during which irreversible organ damage accrues. This review aims to sharpen diagnostic acumen and provide actionable strategies for early recognition and contemporary management.

Pathophysiology: When Proteins Misbehave

Amyloid fibrils share common structural features regardless of their precursor protein: a cross-β-sheet configuration that binds Congo red dye, producing pathognomonic apple-green birefringence under polarized light⁴. However, the clinical syndrome depends entirely on which protein is misbehaving.

In AL amyloidosis, monoclonal immunoglobulin light chains (typically lambda > kappa) produced by a clonal plasma cell population misfold and deposit in tissues. The heart, kidneys, liver, peripheral nerves, and gastrointestinal tract are preferentially affected⁵.

In ATTR amyloidosis, the culprit is transthyretin (TTR), a hepatically-synthesized transport protein for thyroxine and retinol-binding protein. Wild-type ATTR (ATTRwt, formerly "senile cardiac amyloidosis") affects elderly men and deposits predominantly in the heart. Hereditary ATTR (ATTRv) results from one of over 120 TTR mutations, with the Val122Ile variant affecting 3-4% of African Americans⁶—a fact with profound screening implications.

Clinical Presentations: Recognizing the Red Flags

Cardiac Amyloidosis: The Stiff Heart Syndrome

Cardiac involvement dominates the clinical picture in both AL and ATTR and determines prognosis. Classic findings include:

HFpEF phenotype: Dyspnea, fatigue, and exercise intolerance with preserved or mildly reduced ejection fraction
Increased ventricular wall thickness on echocardiography (often symmetric, ≥12mm)
Low-voltage QRS complexes on ECG despite thick ventricular walls—a pathognomonic mismatch⁷
Elevated natriuretic peptides (BNP, NT-proBNP) disproportionate to clinical presentation
Longitudinal strain pattern: Apical sparing on speckle-tracking echocardiography ("cherry-on-top" sign)⁸

Pearl: The combination of increased wall thickness, low QRS voltage, and elevated natriuretic peptides has >85% specificity for cardiac amyloidosis in the absence of severe renal failure⁹.

Oyster: Not all cardiac amyloidosis presents with heart failure. Some patients present with syncope (conduction disease requiring pacemaker), orthostatic hypotension (autonomic neuropathy), or atrial fibrillation with disproportionate symptom burden.

Renal Amyloidosis: The Heavy Proteinuria

AL amyloidosis frequently involves the kidneys, manifesting as:

Nephrotic-range proteinuria (often >5 g/day) with relatively preserved GFR initially
Bland urinary sediment (minimal hematuria or cellular casts)
Large kidneys on imaging (unlike most causes of chronic kidney disease)¹⁰

Hack: In any patient over 50 with new-onset nephrotic syndrome and no diabetic retinopathy, always check serum free light chains before performing a renal biopsy.

Neurologic Amyloidosis: The Dysautonomia Clue

Peripheral and autonomic neuropathy characterize hereditary ATTR (especially in endemic populations with specific mutations like Val30Met):

Bilateral carpal tunnel syndrome (often requiring surgery) in a middle-aged patient
Progressive sensorimotor polyneuropathy (length-dependent, small fiber predominant)
Autonomic dysfunction: Early satiety, alternating diarrhea/constipation, erectile dysfunction, orthostatic hypotension¹¹

Pearl: Bilateral carpal tunnel syndrome preceding systemic symptoms by years should trigger evaluation for hereditary ATTR, especially in patients of Portuguese, Swedish, or Japanese descent.

Other Manifestations

Macroglossia (nearly pathognomonic for AL; seen in ~10% of cases)
Periorbital purpura ("raccoon eyes") after minimal trauma or Valsalva
Shoulder pad sign (amyloid deposition in deltoid)
Hepatomegaly without hepatocellular dysfunction
Non-ischemic cardiomyopathy in patients with "unexplained" HFpEF

Diagnostic Approach: The Modern Algorithm

Step 1: Clinical Suspicion (The Sine Qua Non)

Diagnosis begins with suspicion. Consider amyloidosis in:

HFpEF with increased wall thickness and low QRS voltage
Nephrotic syndrome in patients >50 without diabetes
Unexplained sensorimotor and autonomic neuropathy
Bilateral carpal tunnel syndrome
Restrictive cardiomyopathy of unknown etiology

Step 2: Non-Invasive Screening for AL Amyloidosis

Serum free light chain (sFLC) assay with kappa/lambda ratio is the first-line test¹². An abnormal ratio suggests a clonal plasma cell disorder. Follow with:

Serum and urine protein electrophoresis with immunofixation (SPEP/UPEP with IFE)
Bone marrow biopsy if plasma cell dyscrasia confirmed

Pearl: sFLC may detect monoclonal light chains even when SPEP/UPEP are negative (so-called "light chain escape")¹³. Always order sFLC in suspected AL amyloidosis.

Step 3: Imaging for ATTR Cardiac Amyloidosis

If sFLC is normal and cardiac involvement is suspected, proceed to ⁹⁹ᵐTc-pyrophosphate (PYP) scintigraphy or alternative bone tracers (DPD, HMDP in Europe)¹⁴.

Grade 2-3 cardiac uptake (visual score ≥2 or heart-to-contralateral ratio >1.5) is highly specific for ATTR cardiac amyloidosis if a monoclonal protein has been excluded
Sensitivity approaches 100% for ATTR; false positives rare if AL ruled out¹⁵

Hack: The non-invasive diagnostic algorithm permits diagnosis of ATTR cardiac amyloidosis without biopsy if: (1) Grade 2-3 PYP uptake AND (2) No monoclonal protein on comprehensive screening. This paradigm-shifting approach has been validated in multiple cohorts¹⁶.

Step 4: Tissue Biopsy and Amyloid Typing

When non-invasive testing is inconclusive or extra-cardiac involvement suspected:

Fat pad aspiration (60-80% sensitive, safe, office-based)
Bone marrow biopsy (if plasma cell dyscrasia suspected)
Endomyocardial biopsy (gold standard for cardiac involvement; rarely needed with modern algorithms)
Organ-specific biopsy (kidney, nerve, GI tract) based on presentation

Critical Step: Congo red staining for apple-green birefringence under polarized light confirms amyloid. Amyloid typing via immunohistochemistry, immunofluorescence, or mass spectrometry is mandatory to distinguish AL from ATTR—treatment differs entirely¹⁷.

Oyster: Never assume amyloid type based on clinical presentation alone. Up to 10% of cases initially mistyped lead to inappropriate therapy¹⁸.

Step 5: Genetic Testing for Hereditary ATTR

If ATTR confirmed, TTR gene sequencing is essential to distinguish wild-type from hereditary. Implications include:

Cascade screening of family members
Eligibility for gene-silencing therapies
Prognostic information

The Cardinal Sin: Anticoagulation Without Diagnosis

Do NOT empirically anticoagulate patients with suspected amyloidosis without definitive diagnosis. Amyloid infiltration causes vascular fragility, and anticoagulation (even for atrial fibrillation) carries catastrophic bleeding risk¹⁹.

Fatal GI hemorrhage, intramuscular hematomas, and spontaneous splenic rupture are well-documented
If anticoagulation absolutely required (mechanical valve, proven thromboembolism), use cautiously with close monitoring and gastroenterology consultation

Pearl: Factor X deficiency may occur in AL amyloidosis due to factor X binding to amyloid fibrils—check factor X level before starting anticoagulation²⁰.

Treatment: A New Era of Disease-Modifying Therapies

AL Amyloidosis: Target the Plasma Cell Clone

Treatment parallels multiple myeloma protocols, aiming to eliminate the clonal plasma cell population:

Bortezomib-based regimens (CyBorD: cyclophosphamide, bortezomib, dexamethasone) are first-line²¹
Daratumumab (anti-CD38 monoclonal antibody) increasingly used, especially in relapsed/refractory disease²²
Autologous stem cell transplantation for eligible patients (age <65, good performance status, limited cardiac involvement)²³

Monitoring: Serial sFLC every 1-2 months. Hematologic response (≥50% reduction in involved light chain) predicts organ response and survival²⁴.

Pearl: Organ dysfunction often worsens before improving due to lag between light chain reduction and fibril clearance. Supportive care (heart failure management, renal replacement) is critical during this window.

ATTR Amyloidosis: Stabilizers and Silencers

The therapeutic landscape for ATTR has been revolutionized:

TTR Stabilizers

Tafamidis binds to TTR, preventing tetramer dissociation and fibril formation. The landmark ATTR-ACT trial demonstrated reduced mortality and cardiovascular hospitalization in ATTR cardiac amyloidosis²⁵.

Dose: 61 mg daily (or 80 mg of tafamidis meglumine)
Benefit in both ATTRwt and ATTRv
Approved by FDA for ATTR cardiomyopathy (2019)

Diflunisal (off-label, less expensive alternative) also stabilizes TTR but has NSAID-related side effects²⁶.

Gene Silencers (for ATTRv)

Patisiran (RNA interference) and inotersen (antisense oligonucleotide) reduce hepatic TTR production by >80%²⁷,²⁸.

Indicated for hereditary ATTR polyneuropathy
Dramatic slowing or reversal of neuropathy progression
Patisiran: IV infusion every 3 weeks
Inotersen: Subcutaneous weekly injections (requires monitoring for thrombocytopenia and renal toxicity)

New Kids on the Block: Vutrisiran (next-generation siRNA, quarterly dosing) and eplontersen (antisense with improved dosing) recently approved, offering greater convenience²⁹,³⁰.

Organ Transplantation

Liver transplantation for select ATTRv cases (eliminates source of mutant TTR)
Heart transplantation considered in advanced cardiac amyloidosis, though recurrence may occur in ATTRv without liver transplant³¹

Pearls, Oysters, and Practical Hacks

Diagnostic Pearls

"Low voltage despite thick walls": This ECG-echo mismatch is virtually diagnostic of cardiac amyloidosis
Elevated troponin with normal coronaries: Think infiltrative cardiomyopathy, including amyloidosis
Bilateral carpal tunnel in a 50-year-old: Screen for hereditary ATTR
Nephrotic syndrome + normal kidney size: Always exclude AL amyloidosis

Diagnostic Oysters

Not all amyloid "lights up" on PYP: AL amyloidosis does NOT show significant cardiac uptake—PYP only for ATTR
Atrial fibrillation is common: Present in >60% of cardiac amyloidosis but anticoagulation is dangerous—individualize carefully³²
Diastolic dysfunction alone is not enough: Many conditions cause diastolic dysfunction; look for constellation of findings

Treatment Hacks

Diuretics are your friend: These patients are exquisitely preload-dependent; aggressive diuresis often improves symptoms dramatically
Avoid ACE inhibitors/ARBs early: These may cause profound hypotension in amyloidosis due to autonomic dysfunction and low cardiac output
Beta-blockers and calcium channel blockers: Use cautiously—negative inotropes poorly tolerated in restrictive physiology³³
Digoxin is contraindicated: Binds to amyloid fibrils, increasing toxicity risk³⁴

Prognostic Hacks

Mayo Staging System for AL: Based on NT-proBNP and troponin; predicts survival³⁵
NAC Score for ATTR: Based on NT-proBNP, eGFR, and NYHA class; guides therapeutic decisions³⁶

Screening and Future Directions

Given the prevalence of Val122Ile mutation in African Americans and the high burden of undiagnosed ATTRwt in elderly patients with HFpEF, interest is growing in:

Population screening programs
Biomarker-based algorithms for high-risk cohorts (e.g., all patients >60 with HFpEF and increased wall thickness)
Novel therapeutics: CRISPR-based gene editing, fibril-targeting antibodies, and small molecules to disaggregate existing deposits³⁷

Conclusion: Think Amyloidosis

Amyloidosis is no longer a diagnosis of despair. Early recognition, enabled by high clinical suspicion and modern non-invasive algorithms, coupled with disease-modifying therapies, has transformed outcomes. The internist's role is pivotal: consider amyloidosis in atypical presentations of common syndromes. When HFpEF doesn't behave like HFpEF, when nephrotic syndrome occurs without diabetes, when neuropathy comes with dysautonomia—pause, and think protein misfolding.

As the adage goes: "Amyloidosis is diagnosed by the physician who thinks of it." Let this be you.

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