What are the clinical manifestations of amyloidosis?

Clinical Manifestations of Amyloidosis

Amyloidosis presents with a wide spectrum of clinical manifestations that vary depending on the type of amyloid protein and the organs involved, with cardiac, renal, neurologic, and gastrointestinal systems being most commonly affected. 1, 2

Types of Amyloidosis and Their Manifestations

Primary (AL) Amyloidosis

• Cardiac involvement (up to 50% of cases):

  • Heart failure with preserved ejection fraction initially
  • Restrictive cardiomyopathy pattern
  • Drastically reduced survival (13 months median; 4 months if heart failure present) 1
  • Electrocardiographic abnormalities:
    • Reduced QRS voltage despite ventricular wall thickening
    • Pseudoinfarct pattern in precordial leads
    • Atrial fibrillation
    • Atrioventricular conduction abnormalities 1

• Renal manifestations:

  • Proteinuria (most common)
  • Progressive renal failure 2

• Soft tissue involvement:

  • Macroglossia (enlarged tongue)
  • Submandibular gland enlargement
  • Periorbital purpura
  • Coagulopathy from acquired factor X deficiency 1

• Gastrointestinal manifestations (reported in up to 60% of patients):

  • Early satiety
  • Weight loss
  • Abdominal pain
  • Nausea
  • Constipation and diarrhea 1

Transthyretin (ATTR) Amyloidosis

• Hereditary ATTR (ATTRv):

  • Peripheral and autonomic neuropathy
  • Cardiomyopathy
  • Median survival: 70 months 1

• Wild-type ATTR (ATTRwt, formerly senile):

  • Predominantly cardiac involvement
  • Median survival: 75 months 1
  • GI manifestations comparable to general population 1

• Musculoskeletal manifestations (more common in ATTR):

  • Biceps tendon rupture
  • Spinal stenosis 1, 2

Reactive (AA) Amyloidosis

• Less frequent cardiac involvement (<10%)
• Predominantly kidney and liver involvement
• Median survival: 25 months 1

Dialysis-related Amyloidosis

• Joint involvement
• Carpal tunnel syndrome
• Skeletal manifestations 1

Organ-Specific Manifestations

Cardiac Manifestations

• Initially presents as restrictive cardiomyopathy with diastolic dysfunction
• Progresses to systolic dysfunction in advanced stages
• Increased myocardial stiffness leading to elevated filling pressures
• Normal heart size with normal systolic function in early stages
• Potential pericardial effusion
• Potential coronary artery involvement leading to ischemia 1

Neurologic Manifestations

• Peripheral neuropathy:

  • Small fiber neuropathy (early)
  • Painful sensory symptoms
  • Progressive motor deficits
  • Relentlessly progressive course 3

• Autonomic dysfunction:

  • Orthostatic hypotension
  • Erectile dysfunction
  • Sweating abnormalities
  • Gastrointestinal dysmotility 1

Gastrointestinal Manifestations

• Multiple mechanisms of involvement:

  • Mucosal involvement: malabsorption, protein-losing enteropathy
  • Neuropathic involvement: GI dysmotility
  • Vascular involvement: ischemia and bleeding 1

• Common symptoms:

  • Early satiety
  • Weight loss
  • Abdominal pain
  • Nausea
  • Constipation
  • Diarrhea
  • Small intestinal bacterial overgrowth 1, 4

Renal Manifestations

• Proteinuria (often nephrotic range)
• Progressive renal failure 2, 4

Hepatic Manifestations

• Hepatomegaly
• Mildly abnormal liver tests (elevated alkaline phosphatase) 4

Diagnostic Challenges

• Diagnosis is often delayed due to:

  • Nonspecific and vague symptoms
  • Multiple organ involvement with varying presentations
  • Symptoms mimicking more common conditions 2

• Early recognition is crucial as treatment effectiveness depends on initiating therapy before irreversible organ damage occurs 2

High-Risk Populations for Screening

Consider amyloidosis in patients with:

• Monoclonal gammopathy of undetermined significance (MGUS)
• Unexplained heart failure with preserved ejection fraction
• Unexplained proteinuria
• Peripheral neuropathy of unknown origin
• Hepatomegaly with mildly abnormal liver tests
• Weight loss and GI symptoms without clear etiology 2, 4

Diagnostic Approach

• Tissue biopsy with Congo Red staining (appears red in normal light and apple-green in polarized light) 4
• Echocardiography for suspected cardiac involvement
• Cardiac MRI may show late gadolinium enhancement in the subendocardium 1
• Monoclonal protein screening to differentiate AL from ATTR amyloidosis 1
• Endoscopy and colonoscopy with random biopsies for suspected GI involvement 1

The clinical manifestations of amyloidosis are diverse and often mimic other more common conditions, making early diagnosis challenging but crucial for improving outcomes. A high index of suspicion is needed, particularly in patients presenting with multisystem involvement.