Amyloidosis

Overview

Definition

Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits.

Classification

• Based on the identity of the fibril-forming protein:
  • Systemic amyloidosis (neoplastic, inflammatory, genetic, iatrogenic)
  • Localized amyloidosis (aging, diabetes)
  • Hereditary amyloidosis
• Named with a capital letter A (for amyloid) followed by precursor protein designation (e.g., AL = amyloid light chain)

Etiology

Systemic amyloidosis:

• Light chain amyloid (AL) disease results from disproportionate production of immunoglobulin light chains by plasma cells (lambda > kappa).
• Amyloid A amyloidosis (AA) disease manifests as a systemic complication of inflammatory disease.
• β₂-microglobulin amyloid (Aβ₂M) is observed in the setting of long-term hemodialysis due to inadequate filtration by the dialysis membrane.

Localized amyloidosis:

• Amyloid deposits form in the vicinity of tissues/organs/tumors that produce polypeptide hormones:
  • Calcitonin amyloid (ACal) is associated with medullary carcinoma of the thyroid.
  • Prolactin amyloid (APro) is associated with the aging pituitary.
• Alzheimer’s-associated amyloid (Aβ) disease manifests as deposits in cerebrovascular walls and neuritic plaques in Alzheimer’s disease and Down syndrome.
• Prion protein-associated amyloid (APrP) disease is caused by infectious proteins associated with the transmissible spongiform encephalopathies (Kuru, Creutzfeldt-Jakob disease, etc.).
• Systemic amyloidosis can be observed as localized deposits.

Hereditary amyloidosis:

• Associated with protein mutations
• Abnormal folding → fibril formation (transthyretin amyloid = ATTR, apolipoprotein I amyloid = AApoAI, etc.)

Epidemiology

• Most common systemic cause in clinical practice is AL:
  • > 80% are idiopathic.
  • < 20% are due to multiple myeloma.
    • Multiple myeloma is the most common identifiable cause in clinical practice.
• Most common inflammatory cause in clinical practice is rheumatoid arthritis:
  • 6% of amyloidotic cases are associated with an inflammatory condition.
  • 3% of rheumatoid arthritis patients have an amyloid deposition.
• Most common hereditary cause in clinical practice is ATTR.
• Most common causes of death are heart disease and renal failure.
• AL survival is approximately 12 months after diagnosis.
• Familial amyloidosis survival is approximately 7–15 years after diagnosis.

Pathophysiology

• Misfolded proteins (almost always in β-pleated sheet configuration) aggregate into insoluble fibrils.
• Deposition and amyloid formation within the tissue interferes with tissue physiology.
• Cellular injury and apoptosis results.
• Under “normal” physiologic conditions:
  • Amyloidogenic precursors are not produced in excess.
  • No genetic predisposition for amyloid formation
  • Proteolytic mechanisms exist to degrade excess proteins.
  • Extracellular matrix constituents do not allow protein deposition.
• There are 4 pathophysiologic features common to all types of amyloid formation:
  • Amyloidogenic protein precursors present in excessive concentration
  • Genetic predisposition
  • Inadequate proteolytic mechanisms
  • Abnormalities in extracellular matrix constituents

Clinical Presentation

Clinical presentation depends on the organ/organs involved.

• Heart:
  • Myocardial deposition causes restrictive cardiomyopathy:
    • Symptoms include dyspnea, peripheral edema, and fatigue.
  • Conduction system involvement causes arrhythmia:
    • Symptoms include palpitations, fatigue, syncope, and sudden cardiac death.
• Skin:
  • Raised waxy papules or plaques
  • Found in axillary, anal, and/or inguinal folds
  • Periorbital ecchymosis (also known as “black eyes” or “raccoon eyes”)
• Kidneys:
  • Ranges from mild proteinuria to frank nephrosis
  • Possible progression to azotemia and death
  • Dialysis or transplant improves prognosis.
• Liver:
  • Hepatomegaly is common in most forms of amyloid (except in ATTR).
  • Liver function abnormalities are minimal and occur late in the disease.
• Intestine:
  • GI involvement is common in all systemic amyloidosis. The symptoms could either be direct GI tract infiltration or autonomic nervous system involvement:
    • Symptoms (GI tract):
      • Obstruction, ulceration, malabsorption, and/or hemorrhage
    • Symptoms (GI autonomics):
      • Dysmotility, nausea, vomiting, diarrhea, and/or constipation
• Tongue:
  • Tongue involvement is a common manifestation of AL.
    • Symptoms: stiffened musculature → dysarthria, firmness to palpation → occasional macroglossia → risk for obstructive sleep apnea
• Brain:
  • Cerebrovascular endothelial amyloid deposition in Aβ → increased risk of cerebrovascular accident
  • Neuritic plaque development in Aβ → neurodegenerative changes typical of Alzheimer’s disease
• Peripheral nerves:
  • Peripheral nerve damage (especially in hereditary amyloidosis) with the cranial nerves usually spared:
    • Symptoms (sensory):
      • Numbness, neuropathic pain, paresthesia, dysesthesia, and/or allodynia
    • Symptoms (motor):
      • Weakness, cramping, and/or discoordination
    • Carpal tunnel syndrome is common in AL, Aβ₂M, and ATTR.
  • Autonomic nerve damage (especially in hereditary amyloidosis) with the cranial nerves not spared:
    • Symptoms (CN3):
      • Tonic pupil or Adie’s pupil:
        • CN3 parasympathetic dysfunction (does not dilate in the dark)
    • Symptoms (peripheral):
      • Postural hypotension, urinary retention, sphincter failure, GI dysmotility, and/or loss of sweat reflex
• Musculoskeletal: 
  • Articular involvement is rare, almost exclusively in AL due to multiple myeloma, presents like rheumatic disease with symmetrical small joint involvement.
  • Muscle infiltration → pseudomyopathy, pseudohypertrophy (shoulder involvement → “shoulder pad” sign)
• Hematologic:
  • Factor X binding to amyloid fibrils → splenic sequestration → increased bleeding risk
  • Fibrinogen deficiency, increased fibrinolysis, and an increase in endothelial damage compound bleeding risk.
• Pulmonary:
  • Tracheobronchial infiltration → hoarseness, stridor, and/or airway obstruction
  • Pleural infiltration → pleural effusions
  • Parenchymal nodules
  • Pulmonary hypertension (rare)

Diagnosis and Management

Diagnosis

History and physical exam:

• Family history
• History of hematologic disorders/plasma cell dyscrasias
• Autoimmune conditions (rheumatoid arthritis, Sjogren’s syndrome)
• Nephrotic syndrome in association with another systemic disease
• Physical exam findings may or may not be significant depending on the organs involved.

Tissue biopsy:

• Definitive diagnosis
• Usually abdominal fat, renal, salivary glands, or rectal
• Amorphous extracellular depositions stain red or pink with H&E stain.
• Apple green birefringence under a polarized microscope with Congo red stain
• Biopsy of the specific organ for localized involvement:
  • Muscle, peripheral nerves, and/or skin

Tests specific to the underlying disease: 

• Hereditary amyloidosis:
  • Gene sequencing
• Suspected AL:
  • IgM–associated disorders:
    • Multiple myeloma
    • Waldenstrom’s macroglobulinemia
  • Workup includes:
    • Serum and/or urine electrophoresis
    • Bone marrow biopsy
• Suspected AA:
  • Chronic inflammatory conditions and systemic conditions
  • Workup may include:
    • Rheumatoid arthritis:
      • Rheumatoid factor assay
    • Sjogren’s syndrome:
      • Antibodies SS-A and SS-B

Management

• Varies based on the fibril type and the organs involved.
• Treatment of the underlying cause: 
  • Reduce precursor protein production:
    • Tafamidis:
      • Stabilizes native transthyretin (approved for cardiomyopathy)
    • Patisiran:
      • Inhibits mutant transthyretin production (for polyneuropathy)
  • Inhibit extracellular protein deposition:
    • Daratumumab/hyaluronidase for AL amyloidosis
  • Promote proteolysis or mobilization of existing deposits:
    • Gantenerumab:
      • An antibody that binds to aggregated Aβ
    • Tocilizumab:
      • Used for arthritis
• Supportive treatment (e.g., symptomatic management of organ decompensation)
• Hemodialysis for renal involvement
• Colchicine for familial Mediterranean fever (AA)
• Melphalan, iododoxorubicin, and alkylating agents for plasma cell dyscrasias (AL)
• Stem cell transplantation for AL due to multiple myeloma
• Splenectomy for Factor X deficiency
• Organ transplantation once tissue deposition has been confirmed

Differential Diagnosis

• Membranous nephropathy: a nephrotic syndrome associated with glomerular basement membrane thickening. This condition presents with proteinuria, weight gain, and/or lower extremity edema. Diagnosis is established with renal biopsy or serological studies. Treatment is mostly supportive but can include immunosuppressants in severe cases.
• Cutis verticis gyrata: the thickening and folding of the scalp skin, which may occur in association with amyloidosis or other diseases. However, cutis verticis gyrata can be a primary condition. Diagnosis is established clinically and a workup for associated conditions is usually performed. Treatment for a primary condition involves cosmetic surgical procedures.
• Mastocytosis: an excessive mast cell accumulation in 1 or multiple organs. This condition can involve skin (primarily) or multiple organs. Symptoms depend on the organs involved and can include maculopapular rash, abdominal pain, vomiting, diarrhea, neuropsychiatric manifestations, and/or myalgias. Diagnosis is established with skin and bone marrow biopsy. Treatment is mostly with medications.
• Pseudoxanthoma elasticum: the ectopic mineralization and fragmentation of elastic fibers in the skin, eyes, vascular system, and/or GI system. This condition presents with characteristic skin changes and eye/cardiovascular manifestations. Diagnosis is established from a combination of clinical findings, skin biopsy, and genetic testing. Management is mostly supportive.