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Amyloidosis

Classification
  • Systemic
    • Primary (plasma cell dyscrasia)
    • Secondary (inflammatory due to rheumatoid arthritis, autoinflammatory disease, chronic infections)
  • Localized
    • Cutaneous only
    • Proteins mostly keratin filaments made in keratinocytes (exception nodular amyloidosis)
    • Primary: macular, lichen, biphasic, nodular
    • Secondary: within skin tumors (incidental finding, due to keratin protein)
  • Familial syndromes with associated amyloidosis (AA protein)
 
Amyloid: fibrillar proteinaceous material that deposits in tissues.
  • There are several types, that share common properties
  • Crossed beta pleated sheet configuration
  • 3 main types
    • AA (amyloid-associated, non-immunoglobulin)
      • Produced by the liver
      • Seen in chronic systemic inflammatory conditions
    • AL (immunoglobulin Light chain)
    • Keratin
    • β2-microglobulin
      • notion image
 
Stains for Amyloid
  • Congo red (green birefringence with polarized light)
  • PAS
  • Thioflavin T - requires fluorescent microscope
  • Crystal violet
 

Primary Cutaneous Amyloidosis

  • Macular amyloidosis and Lichen amyloidosis
    • Macular and Lichen Amyloid are in a spectrum and you can see both in one lesion - called “biphasic amyloidosis”
    • Most common on the upper back, then extensor surfaces of extremities, usually as a result of chronic scratching
    • Macular type presentation: wrippled hyperpigmentation
    • Lichen amyloidosis is the most common type
      • Usually on the shins or other extensor surfaces of extremities
      • Usually a result of chronic scratching
      • Presentation: numerous monomorphic papules with wrippled appearence
      • DDx: lichen simplex chronicus (would have a purplish hue), papular mucinosis, pre-tibial myxedema and prurigo
          • notion image
    • Both are made of keratin protein and can be a sign of MEN2A - suspect if appears in childhood
  • Nodular amyloidosis
    • Very rare
    • Made of AL protein (light chain)
    • Small chance (7%) of progressing to systemic involvement → routine follow-up indicated
    • Plasma cell proliferation in the dermis → deposition of IgG and light chains
    • Clinical Presentation
      • Single or multiple waxy nodules or plaque on the trunk or extremities
      • Ill-defines yellowish plaques
      • Anywhere on the body
    • DDx: dermal inflammatory disorders or dermal deposition disorders
      • Lymphoma cutis, pseudolymphoma, pre-tibial myxedema, sarcoidosis, granuloma anulare, reticulohistiocytosis, granuloma faciale
  • Primary cutaneous amyloidosis Associations
    • Notalgia parasthetica
    • Connective tissue disease
      • MEN2A - Sipple Syndrome (RET gene)
      • Autosomal dominant
      • Pruritic hyperpigmented areas of lichen or macular amyloydosis on the upper back in childhood (<10yo) - notalgia pararasthetica-like
        • Lichen or macular amyloidosis present in 36% of MEN2A cases. All with cutaneous amyloidosis have mutation on codon 634 of RET protooncogene
      • Associations:
        • Medullary thyroid cancer
        • Pheochromocytoma
        • Hyperparathyroidism
      • Recognition of this sign can lead to prophylatic thyroidectomy when diagnosis is established
    • Pachyonychia congenita
    • Familial Primary Localized Cutaneous Amyloidosis
      • Mutation in OSMR β protein or IL-31R
      • Autossomal dominant
      • Chronic localized itching and scratiching that results in deposition of keratin-derived amyloid in the dermis
      • Vixarelimab → monoclonal antibody against OSMRβ under investigation for prurigo nodularis
    • Familiar palmoplantar keratoderma
  • Pathophysiology
    • Il-31 signalling is overactive in primary cutaneous amyloidosis → part of the itch pathway → nemolizumab may be used as treatment
  • Treatment
    • Potent topical steroids
    • Topical calcineurin inhibitors
    • Intralesional steroids
    • Occlusive dressings
    • Phototherapy (UVB or PUVA)
    • Systemic retinoids
    • Dermabrasion
    • CO2 laser
    • Low dose cyclophosphamide
    • Cyclosporine
 

Primary Systemic Amyloidosis

  • Underlying plasma cell dyscrasia
    • AL protein deposition in the skins, λ chains in 75-80% (similar to nodular amyloidosis)
  • Skin manifestations
    • 25% have skin involvement
    • Mucosal infiltration - big tongue with identations from the teeth
    • “Pinch purpura” - amyloid deposition in blood vessels → hemorrhage when area is rubbed
      • Petechiae, purpura, echymosis specially around the eyelids, neck, axillae, anogenital region (due to pruritus leading to trauma)
      • Raccon eye sign - periorbital purpura, may be precipitated by coughing
    • Waxy translucent papules
  • Extracutaneous manifestations
    • Carpal tunnel syndrome
    • Renal, cardiac, neural, and hepatic involvement
      • Renal → proteinuria, hypoalbuminemia, edema
      • Heart → CHF, dypnea, elevated JVD
      • Hepatomegaly in 50% of patients
      • Bilateral symmetrical sensory neuropathy
      • Autonomic neuropathy → orthostatic hypotension, impotence, impaired GI motility
  • Workup
    • Always check abnormalities of light chains in blood and urine
    • Abdominal fat aspiration or punch biopsy for diagnosis
      • notion image

Secondary Systemic Amyloidosis

  • Complication of chronic inflammation - AA protein
    • Infections: TB, lepromatous leprosy
    • Chronic inflammatory diseases: RA, ankylosing spondilitis, HS, dystrophic epidermolysis bullosa, generalized psoriasis, chronic pustular psoriasis, scleroderma, dermatomyositis, systemic lupus erythematosus
    • Autoinflammatory diseases
  • Deposition of a distinctive non-immunoglobulin derived AA protein, usually produced by the liver

Muckle-Wells Syndrome

  • Familial disorder that leads to secondary systemic amyloidosis
  • Fever
  • Limb pains
  • Urticaria-like eruption
  • Progressive deafness
  • AA amyloid nephropathy

Familial Mediterranean Fever

  • Autoinflammatory condition that can lead to secondary systemic amyloidosis
  • Autosomal recessive - mutation in pyrin gene
  • Ethnic groups: arabic, Sephardic Jews, armynian
  • Recurrent fever that last 1-2 days
  • Episodes of pleuritis, peritonitis or synovitis (polyserositis)
  • Erysipelas-like erythema
  • Small vessel vasculitis
  • Treat with colchicine
    • Treats underlying disease
    • Prevents amyloidosis, polyserositis
  • Pyrin gene mutation