What are the symptoms of Amyloidosis?

Symptomatology of Amyloidosis

Amyloidosis presents with highly variable symptoms depending on which organs are affected, but cardiac involvement (heart failure with preserved ejection fraction), renal involvement (nephrotic syndrome with proteinuria), and gastrointestinal symptoms (weight loss, diarrhea, early satiety) are the most common and clinically significant manifestations that drive morbidity and mortality. 1, 2

Cardiac Manifestations

The heart is one of the two most frequently affected organs and is the main driver of mortality in amyloidosis. 1, 2

• Heart failure with preserved ejection fraction (HFpEF) with restrictive features is the hallmark cardiac presentation 2
• Dyspnea, fatigue, and exercise intolerance are the primary cardiac symptoms 2
• Cardiac involvement manifests as restrictive cardiomyopathy in both AL and ATTR types 1

Renal Manifestations

The kidneys are the second most frequently affected organ in systemic AL amyloidosis. 1

• Nephrotic range proteinuria is the characteristic renal presentation, manifesting as edema, foamy urine, and hypoalbuminemia 2, 3
• Approximately 70% of patients with AL amyloidosis have renal involvement with severe nephrotic syndrome, significant proteinuria, and anasarca 3
• Progressive renal dysfunction occurs, with 50% of patients with proteinuria eventually progressing to end-stage renal disease 3

Gastrointestinal Manifestations

GI symptoms are reported in up to 60% of patients with AL amyloidosis and 63% of patients with ATTRv amyloidosis. 1

• Unintentional weight loss is extremely common and often profound 1, 2
• Early satiety is one of the most common GI symptoms 1
• Chronic diarrhea or alternating diarrhea and constipation, particularly night diarrhea 2
• Abdominal pain and nausea are frequently reported 1
• Malabsorption, bloating, and vomiting can occur from mucosal involvement 1
• GI dysmotility from neuropathic involvement of the enteric nervous system 1

Important caveat: GI symptoms do not necessarily correlate with the degree of GI tract infiltration on biopsy—symptoms are reported far more frequently than biopsy-confirmed involvement (60% vs 3-15% in AL amyloidosis). 1

Neurologic Manifestations

Peripheral and autonomic neuropathy are common, particularly in ATTRv and AL amyloidosis. 1, 2, 4

• Distal sensory symptoms beginning symmetrically in toes and feet: numbness, paresthesias, burning pain, and dysesthesias 2, 4
• Symptoms worsen at night or end of day 2
• Progressive weakness starting in toe extensors and ankle dorsiflexors 2
• Autonomic dysfunction with severe manifestations including orthostatic hypotension, gastroparesis, and bladder dysfunction 4
• The relentlessly progressive nature with motor, painful sensory, and severe autonomic dysfunction is a distinct characteristic 4

Soft Tissue and Organ-Specific Manifestations

AL Amyloidosis-Specific Features

These manifestations are most often observed in AL amyloidosis and help distinguish it from ATTR amyloidosis: 1

• Macroglossia (enlarged tongue) and submandibular gland enlargement from soft tissue involvement—pathognomonic when present 1, 2
• Periorbital purpura (periorbital ecchymoses) 1
• Coagulopathy from acquired factor X deficiency 1
• Liver involvement 1
• Lymph node involvement 1

ATTR Amyloidosis-Specific Features

These musculoskeletal manifestations are most often indicative of ATTR amyloidosis: 1

• Biceps tendon rupture 1
• Spinal stenosis 1
• Carpal tunnel syndrome (bilateral) is common in ATTR 4

Constitutional Symptoms

• Profound fatigue affecting quality of life 2
• Unexplained weight loss, often severe and progressive 2

Key Clinical Patterns by Amyloid Type

AL Amyloidosis Pattern

• Heart and kidneys are the two most frequently affected organs 1
• Soft tissue, liver, GI tract, autonomic and peripheral nervous systems, and lymph nodes are also commonly involved 1
• GI symptoms reported in up to 60% of cases 1

ATTRv Amyloidosis Pattern

• 63% report GI symptoms at enrollment, most commonly unintentional weight loss and early satiety 1
• GI symptoms more predominant in neuropathic variants 1

ATTRwt Amyloidosis Pattern

• Predominantly cardiac involvement 1
• GI manifestations comparable to the general population (not increased) 1

Critical Diagnostic Considerations

The clinical presentation varies widely and is often nonspecific, depending on which organs or tissues are affected, making early diagnosis challenging. 5, 6, 7

• Symptoms may be subtle initially and progress relentlessly 6, 4
• Early diagnosis is of paramount importance for effective treatment and prognosis due to the progressive nature of the disease 6
• High-risk populations (particularly MGUS patients) benefit from regular screening with NT-proBNP and albuminuria monitoring before overt symptoms develop 2