Amyloidosis

Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). These misfolded proteins can become deposited in different tissues, interfere with normal organ functions, and cause tissue-specific diseases (e.g., renal amyloidosis causes proteinuria). Diagnosis is established clinically and confirmed with tissue biopsy. Treatment should be directed toward the underlying cause and the reduction of amyloid deposition.

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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

Types of Amyloidosis

Systemic amyloidosis

  • AL: 
    • Precursor is immunoglobulin light chains (lambda type).
    • Associated with plasma cell dyscrasias (e.g., multiple myeloma, Waldenstrom’s macroglobulinemia)
  • AA: 
    • Precursor protein is serum amyloid A protein.
    • Produced by the liver in response to cytokines (e.g., IL-1)
    • Associated with chronic inflammatory conditions and infections (e.g., rheumatoid arthritis, osteomyelitis)
  • Aβ₂M:
    • β₂-microglobulin is the precursor protein.
    • Associated with chronic hemodialysis
    • ↑ β₂-microglobulin concentration due to inefficient filtration through dialysis membranes
Table: Systemic amyloidosis and the major organ systems affected
DiseaseAmyloid proteinOrgans involvedSpecifics
Primary amyloidosisALSystemic involvement:
  • Heart
  • Kidney
  • Liver
  • Spleen
  • Skin
  • Nerves
  • Tongue
Secondary amyloidosisAA
Hemodialysis-associated amyloidosisAβ₂M
  • Synovium
  • Joints
  • Tendon sheaths
  • Patients on long-term dialysis
  • Associated with carpal tunnel syndrome

Localized amyloidosis

  • Aβ:
    • Precursor protein is a novel β protein.
    • Associated with Alzheimer’s disease and Down syndrome
    • Deposits mainly around cerebral blood vessels and neuritic plaques
  • ACal:
    • Precursor protein is calcitonin.
    • Associated with thyroid medullary carcinoma
    • Deposits in the thyroid gland
  • AIAPP:
    • Precursor protein is islet amyloid polypeptide (IAPP) or amylin.
    • Associated with type 2 diabetes mellitus
    • Deposits in the pancreas
  • AANP:
    • Precursor protein is atrial natriuretic peptide.
    • Causes isolated atrial amyloidosis
    • Deposits in the atria → affect electrical conduction → arrhythmia
Table: Localized amyloidosis and the major organ systems affected
DiseaseAmyloid proteinOrgans involvedSpecifics
Cerebral amyloidosisAβ amyloid
  • Walls of the cerebral vessels
  • Neuritic plaques
  • Alzheimer’s disease
  • Down syndrome
Medullary carcinoma of the thyroidACalThyroid glandClinically insignificant
Type 2 diabetes mellitusAIAPPPancreatic islets of LangerhansAssociated with insulinoma
Isolated atrial amyloidosisAANPAtriaAssociated with aging

Hereditary amyloidosis

  • AA:
    • Associated with familial Mediterranean fever
  • ATTR:
    • Precursor protein is mutated transthyretin.
    • Associated with familial amyloid neuropathy and familial amyloid cardiomyopathy
    • Deposits in peripheral nervous system, autonomic nervous system, and myocardium
Table: Hereditary amyloidosis and the major organ systems affected
DiseaseAmyloid proteinOrgans involvedSpecifics
Familial Mediterranean feverAA
  • Kidneys
  • Liver
  • Spleen
  • Autosomal recessive disease
  • Recurrent abdominal pain, fever, and arthralgias
Familial amyloid neuropathyATTRPeripheral nerves
  • Autosomal dominant disease
  • Peripheral neuropathy
Familial amyloid cardiomyopathyATTRVentricles
  • Autosomal dominant disease
  • Restrictive cardiomyopathy

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)

Systemic manifestations of AL amyloidosis:
A: macroglossia with lateral scalloping of the tongue
B: bilateral periorbital purpura
C: pseudo-athletic appearance secondary to diffuse muscular infiltration
D: voluminous hepatomegaly due to primary hepatic amyloidosis
E: diffuse bilateral interstitial lung disease
F: submandibular gland enlargement
Localized AL amyloidosis:
G: nodular conjunctival amyloidosis
H: laryngeal supraglottic amyloid lump

Image: “Al amyloidosis” by Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A. License: CC BY 2.0

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.

References

  1. Bustamante J.G., & Zaidi S.R.H. (2020). Amyloidosis. Retrieved February 20, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470285/
  2. Gorevic, P. (2020). Overview of Amyloidosis. Retrieved February 17, 2021, from https://www.uptodate.com/contents/overview-of-amyloidosis
  3. Iadanza, M. G., Jackson, M. P., Hewitt, E. W., Ranson, N. A., & Radford, S. E. (2018). A new era for understanding amyloid structures and disease. Nature Reviews Molecular Cell Biology. 19(12), 755–773. https://doi.org/10.1038/s41580-018-0060-8
  4. Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., & Loscalzo, J. (2018). Harrison’s principles of internal medicine (20th edition), pp. 2024-2029. New York: McGraw Hill Education.
  5. Kyle RA. (2001). Amyloidosis: a convoluted story. British Journal of Haematology. 114(3), 529–538. https://doi.org/10.1046/j.1365-2141.2001.02999.x
  6. Lee, A. (2020). Tonic Pupil. Retrieved February 17, 2021, from https://www.uptodate.com/contents/tonic-pupil

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