What are the clinical features and organ involvement in amyloidosis?

Clinical Features and Organ Involvement in Amyloidosis

Amyloidosis presents as a multisystem disease with cardiac involvement being the primary driver of mortality, followed by renal, gastrointestinal, and nervous system manifestations that vary significantly by amyloid protein type. 1, 2

Cardiac Manifestations

Heart failure with preserved ejection fraction (HFpEF) with restrictive cardiomyopathy is the hallmark cardiac presentation, starting with diastolic dysfunction and progressing to severe systolic dysfunction in advanced stages. 1, 2

Clinical Presentation

• Dyspnea, fatigue, and exercise intolerance are the primary cardiac symptoms, with median survival dropping drastically to 4 months once heart failure symptoms develop in AL amyloidosis. 1, 2
• Conduction abnormalities including atrioventricular block occur commonly due to infiltration of the conduction system. 1
• Atrial tachyarrhythmias and atrial fibrillation result from amyloid deposition in the atrial wall and atrial dilation from elevated filling pressures. 1

Electrocardiographic Features

• Low QRS voltage in limb leads despite ventricular wall thickening on imaging (present in ~50% of patients). 1
• Pseudoinfarct pattern in precordial leads. 1

Cardiac Involvement by Type

• AL amyloidosis: Up to 50% cardiac involvement with median survival of 13 months (4 months with heart failure). 1
• ATTR amyloidosis (senile): Common cardiac involvement with median survival of 75 months. 1
• Hereditary ATTR: Variable cardiac involvement with median survival of 70 months. 1

Renal Manifestations

Nephrotic range proteinuria is the characteristic renal presentation, manifesting as edema, foamy urine, and hypoalbuminemia. 2

• Approximately 70% of AL amyloidosis patients have renal involvement. 2
• 50% of patients with proteinuria eventually progress to end-stage renal disease. 2
• Renal involvement is common in AL, hereditary, and AA amyloidosis but rare (<10%) in reactive (AA) type. 1

Gastrointestinal Manifestations

GI symptoms occur in up to 60% of AL amyloidosis patients and 63% of ATTRv amyloidosis patients, with profound unintentional weight loss being extremely common. 2, 3

Common GI Symptoms

• Early satiety, chronic diarrhea or alternating diarrhea and constipation, abdominal pain, and nausea. 2, 3
• Malabsorption and steatorrhea particularly in AA amyloidosis due to mucosal involvement. 3, 4
• Constipation, mechanical obstruction, or chronic intestinal pseudo-obstruction in AL amyloidosis due to deposition in muscularis layers. 3, 4

Endoscopic Patterns

• AL amyloidosis: Polypoid protrusions and thickening of valvulae conniventes from deposition in muscularis mucosae, submucosa, and muscularis propria. 3
• AA amyloidosis: Fine granular appearance, mucosal friability, and erosions from granular deposition in propria mucosae. 3

Nervous System Involvement

Peripheral neuropathy with autonomic features is characteristic, particularly in hereditary ATTR amyloidosis. 5, 6

• Autonomic neuropathy causes orthostatic hypotension, gastroparesis, and bladder dysfunction. 1, 2
• Peripheral sensory and motor neuropathy progresses distally to proximally. 1, 2
• Carpal tunnel syndrome is common in AL and dialysis-related amyloidosis. 1

Hepatic Involvement

Hepatomegaly with mildly elevated alkaline phosphatase is the typical presentation, though clinical manifestations are usually mild. 1, 4

• Liver involvement is common in AL and AA amyloidosis. 1
• Significant hepatic dysfunction is rare despite frequent organ involvement. 4

Pathognomonic Soft Tissue Manifestations

Macroglossia and periorbital purpura are pathognomonic for AL amyloidosis when present and should trigger immediate evaluation. 2, 6

AL Amyloidosis-Specific Features

• Macroglossia and submandibular gland enlargement from soft tissue infiltration. 2, 6
• Periorbital purpura (most characteristic dermatologic finding). 2, 6
• Skin involvement including waxy papules and nodules. 1, 2
• Coagulopathy with easy bruising from acquired factor X deficiency. 2, 6

ATTR Amyloidosis-Specific Features

• Biceps tendon rupture is indicative of ATTR amyloidosis. 2
• Spinal stenosis occurs in ATTR amyloidosis. 2
• Skin involvement does NOT occur in ATTR amyloidosis (distinguishing feature). 2

Musculoskeletal Manifestations

• Bilateral carpal tunnel syndrome is a red flag symptom, particularly in AL and dialysis-related amyloidosis. 1, 6
• Joint involvement with arthropathy in dialysis-related amyloidosis. 1
• Skeletal involvement in dialysis-related (β2-microglobulin) amyloidosis. 1

Constitutional Symptoms

Profound fatigue and unexplained weight loss are common constitutional symptoms that significantly affect quality of life across all amyloid types. 2

Critical Clinical Patterns by Amyloid Type

AL (Primary) Amyloidosis

• Heart and kidneys are the two most frequently affected organs. 2
• Additional involvement: liver, nervous system, skin, GI tract, soft tissues, and lymph nodes. 1, 2
• Worst prognosis: Median survival 13 months (4 months with heart failure). 1

ATTR Amyloidosis

• ATTRwt (senile): Predominantly cardiac involvement with median survival of 75 months. 1
• ATTRv (hereditary): Variable cardiac involvement, prominent peripheral and autonomic neuropathy, with GI symptoms more predominant in neuropathic variants. 1, 2
• Median survival 70 months for hereditary forms. 1

AA (Reactive) Amyloidosis

• Kidney and liver are primary targets with <10% cardiac involvement. 1
• Associated with chronic inflammatory diseases (rheumatoid arthritis, Crohn's disease, ulcerative colitis). 5, 7
• Median survival 25 months. 1

Dialysis-Related Amyloidosis

• Joints, carpal tunnel syndrome, and skeletal system are primary targets. 1
• Cardiac involvement unknown. 1

Isolated Atrial Amyloidosis

• Limited exclusively to the heart with no extracardiac manifestations. 1

Key Clinical Pitfalls

Delayed diagnosis occurs when physicians fail to consider amyloidosis due to nonspecific and vague symptoms—maintain high suspicion in patients with unexplained proteinuria, restrictive cardiomyopathy, peripheral neuropathy with autonomic features, bilateral carpal tunnel syndrome, hepatomegaly, macroglossia, or periorbital purpura. 6, 4

Overlooking cardiac involvement is a critical error since heart involvement drives prognosis and mortality regardless of amyloid type. 5, 2