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Amyloidosis Flashcards

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1
Q

What are the classifications of amyloidosis

A
  • Primary Organ
    • Primary cutaneous –> deposites are derived from keratin (macular, lichen, biphasic) or immunoglobulin light chains (nodular)
      • Macular
      • Lichenoid
      • Mixed
      • Nodular
      • Can also get secondary —> within a tumour
    • Thyroid
    • Cerebral
      • Alzheimers
  • Systemic
    • Primary
      • Secondary to haematological malignancy - often multiple myeloma
    • Secondary
      • Seen in inflammatory conditions such as RA
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2
Q

Background info re amyloid

A
  • Amyloid is made up of:
    • Major: fibril protein
    • Minor: amyloid P, glycosaminoglycans, apoE lipoprotein
  • 30 types of amyloid fibril have been identified
  • Important ones for you to know:
    • AL: amyloid light chains - Ig light chains
    • AA: amyloid associated - composed of an acute phase protein synthesized by the liver
    • A-beta: found in cerebral lesions of AD
    • ATTR: familial amyloidosis and senile systemic amyloidosis
  • Amyloid precursors are soluble –> undergo changes leading to aggregation, polymerization, fibril foramtion and finally extracellular tissue deposition
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3
Q

Pathogenesis of primary systemic amyloidosis

A

changes to immunoglobulin light chain destabilizes chains and increases likelihood of conversion to amyloid fibrils

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4
Q

Pathogenesis of primary cutaneous amyloidosis

A
  • Macular and lichenoid variants thought to have precursor derived from keratinocytes
  • Theory: keratinocyte tonofilaments undergo degeneration –> pass into dermis –> modified by histiocytes and fibroblasts –> become amyloid
  • Another theory: that the material is produced at the DEJ
  • Small fibre neuropathy –> likely from pruritus
  • Associated with prolonged friction, genetic predisposition, EBV, environmental
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5
Q

Pathogenesis in nodular amyloidosis

A
  • amyloid deposits are of Ig light chains –> plasma cell derivation
  • local cutaneous production of light chains postulated
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6
Q

Amyloid properties

A
  • Amorphous, eosinophilic fissured masses
  • Congo red: orange-red colour
  • Polarized light: green birefringence
  • Other stains: crystal violet, methyl violet, PAS, Sirius red, pagoda red, Dylon stain, Thioflavin T
  • AA loses its affinity for Congo red after exposure to potassium permanganate
  • Electron microscopy: 7-10 nm wide, non-branching, non-anastomosing fibrils
  • X-ray crystallography and infrared spectroscopy: cross beta-pleased sheet conformation –> identical for all types of amyloid
  • Immunohistochemistry can help determine the different types of amyloid
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7
Q

Histologic criteria used to define amyloid

A

Homogenous, hyaline, eosinophilic deposits in H&E stained sections
Crystal violet metachromasia
Positive staining with Congo red
Apple green birefringence under polarized light after congo red staining
Fibrillar structure on electron miscroscopy
Stains brightly by UV fluoerescence microscopy after Thioflavin T staining
Staining with antibodies to amyloid P component
Staining with antibodies directed against specific precursors

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8
Q

Primary cutaneous amyloidosis epidemiology

A
  • F>M
  • More common in South East Asian countries
  • Lichen amyloidosis more common in Chinese descent
  • Macular seen in Central and South American countries
  • Macular and lichenoid associated with skin phototypes 3 and 4
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9
Q

Primary cutaneous amyloidosis pathogenesis

A
  • In macular and lichenoid, it is believed to be due to an error in the local site where as nodular is due to plasma cell issues
  • Abrasion —> exfoliating significantly can result in lichenoid amyloidosis
  • Not really familial
  • 7% of nodular can evolve to systemic
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10
Q

Macular amyloidosis clinical features

A
  • hyperpigmented, either confluent or rippled pattern
    • Appreciate by stretching the skin
    • Upper back, particularly over scapular, followed by extensor surfaces of the extremities
    • Linear or naevoid pattern seen
    • Early adulthood
    • F>M
    • Biphasic: fine papules superimposed on background of hyperpigmentation

Macular and papular (or lichenoid) –> believed to be 2 ends of a clinical spectrum, sometimes can be present together

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11
Q

Friction amyloidosis clinical

A

: subgroup of patients who have overlap of macular and amyloidosis, and pigmented notalgia paraesthetica –> from friction

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12
Q

Lichen amyloidosis clinical

A
  • Most common form
  • persistent, pruritic plaques on the shins or other extensor surfaces
  • Initial lesions: discrete, firm, scaly, skin-coloured or hyperpigmented papules
  • Can coalesce into plaques with rippled or ridges pattern
  • Usually unilateral initially, then become bilateral symmetric
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13
Q

Other variants of cutaneous amyloidosis

A
  • Ano-Sacral variant: pigmentation and lichenification of anal and sacral region, but often have amyloidosis elsewhere
  • Bullous variant
  • Dyschromic amyloidosis: guttate leukoderma superimposed on background of hyperpigmentation, admixed lesions of macular and lichen amyloidosis
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14
Q

Primary cutaneous amyloidosis associations

A
  • Autoimmune CT disorder: SS, SLE, DM
  • Primary biliary cirrhosis
  • Genetic: Sipple syndrome, mutations in IL-31 as well, pachyonychia congenita, dyskeratosis congenita, familial PPK
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15
Q

Nodular amyloidosis clinical

A
  • Rare
  • single or multiple waxy nodules or infiltrated plaques
  • Trunk or extremities
  • Ig gamma and beta-2 microglobulin have been demonstrated within deposits in this type of cutaneous amyloidosis
  • both are thought to be produced by plasma cells in the vicinity of deposits
  • Associations: Sjogren syndrome, nodular amyloidosis of skin or lung
  • Risk of progression: turning into systemic ~7% so need ongoing monitoring
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16
Q

Investigations for primary cutaneous amyloidosis

A
  • Indicates amyloid deposition in the dermis —> characterised by fissure
  • For nodular —> amyloid deposition also peri-vascular
  • Special stains: Congo Red, under polarised light goes green
17
Q

Histology for primary cutaneous amyloidosis

A
  • Macular and lichen:
    • Amyloid in upper dermis, particularly papillary dermis
    • Lichen: deposits may expand the papillae and displace elongated rete ridges laterally
    • Epidermis: acanthosis, compact orthohyperkeratosis (features of chronic rubbing)
    • Minimal lymphohistiocytic infiltrate can be seen
    • Melanophages
  • Nodular
    • Dermis, subcutis and BV walls are diffusely infiltrated with amyloid
    • Peri-vascular infiltrate of plasma cells may also be seen
    • Immunostain for light chain deposition
    • Suggested may represent unusual variant of cutaneous marginal zone lymphoma
18
Q

Ddx for macular amyloidosis

A
  • Notalgia paresthetica - has melanophages but no amyloid deposits
  • Pit versicolor
  • Atrophic lichen planus
  • Erythema dyschromicum perstans
  • Drug-induced pigmentation
19
Q

Ddx for lichen amyloidosis

A
  • LSC
  • Hypertrophic LP
  • Papular mucinosis
  • Pretibial myxoedema
  • Prurigo simplex/nodularis
  • Pemphigoid nodularis
  • Keratosis lichenoides chronica
  • Colloid milium
  • EB pruriginosa
20
Q

Ddx for nodular amyloidosis

A
  • Cutaneous lesions of primary systemic amyloidosis
  • Lymphoma cutis
  • Cutaneous lymphoid hyperplasia
  • Pretibial myxoedema
  • Sarcoidosis
  • GA
  • Reticulohistiocytosis
  • Granuloma faciale
21
Q

Treatment for primary cutaneous amyloidosis

A
  • General skin care measures - stop exfoliating, breaking the itch-scratch cycle
  • Potent topical steroids under occlusion, +/- with a mild keratolytic agent such as salicylic acid
  • Apply occlusive dressings: hydrocolloids, gauze wraps impregnated with zinc oxide
  • Case reports: calcineurin inhibitors
  • UVB or PUVA: greater improvement with roughness
  • Dermabrasian: helpful when involving the limbs
  • CO2 or Erb Yag therapy - beneficial for macular and lichen
  • Acitretin: improves pruritus and flattens lesions, some clearance of associated hyperpigmentation
  • Preliminary study: cyclophosphamide 50 mg daily –> reduces pruritus and papules in lichen amyloidosis
  • Nodular:
    • Surgical excision
    • Cryotherapy
    • Electrodessication
    • CO2 laser
  • Attempts to harness immunotherapy to get to the amyloid deposited
The list:
steroids
calcineurin inhibitors
IL steroids
occlusive dressings
UVB phototherapy
PUVA phototherapy
systemic retinoids
dermabrasion
CO2 laser
Low dose cyclophosphamide
Cyclosporine
22
Q

Secondary cutaneous amyloidosis clinical

A
  • Amyloid deposits that are inapparent clinically, but seen on histology
  • Seen in dermatofibromas, intradermal melanocytic naevi, seb ks, pilomatricomas, trichoepitheliomas, sweat gland tumours, BCCs, Bowens, porokeratosis, PUVA therapy
23
Q

Primary Systemic Amyloidosis association

A
  • Secondary to a plasma cell dyspraxia, often multiple myeloma, but patients don’t always fulfill the criteria for multiple myeloma
  • Fibrils: AL protein - immunoglobulin light chains, usually upside down V type (75-80%)
  • Results in amyloid deposition in lots of areas
24
Q

Primary Systemic Amyloidosis clinical - mucocutaneous

A
  • Mucous membranes:
    • Soft rubbery swellings or infiltation of mucosa
    • Uniformly enlarged tongue, and firm
    • Haemorrhagic papules, plaques and blisters
    • Surface may be yellow-brown in colour
    • Xerostomia: infiltration of the salivary glands
  • Cutaneous:
    • Petechiae, purpura and ecchymoses –> eyelids, neck, axillae, anogenital region. This is due to amyloid infiltration of the vessel walls
    • Raccoon eyes: precipitated by coughing, Valsalva, protoscopy
    • Pinched purpura
    • Primary systemic amyloidosis: seen in ~25% of individuals –> waxy, translucent or purpuric papules, nodules and plaques that resemble nodular amyloidosis.
      • Palms and volar aspects of fingers: erythematous waxy infiltation
      • Face, neck, scalp, anogenital: smooth, skin-coloured papules, a few mm in diameter
    • Sclerodermoid: less common, can cause scalp skin to be thrown into folds resembling cutis verticis gyrata with associated alopecia
    • Bullous: looking like PCT and EBA may be the initial sign of disease
    • Acquired cutis laxa: rare
    • Macroglossia + carpal tunnel syndrome: classic presentation, should trigger investigation for amyloidosis
  • Nails:
    • Nail dystrophy, often resembles lichen planus - longitudinal ridging and thinning (amyloid in dermis of nail bed and matrix)
25
Q

Primary Systemic Amyloidosis - non-cutaneous features

A

Non-specific: fatigue, weight loss, paraesthesias, dyspnoea, syncopal attacks due to orthostatic hypotension

  • Renal:
    • Proteinuria (albuminuria) –> hypoalbuminaemia and oedema –> nephrotic syndrome
  • Cardiac:
    • Restrictive cardiomyopathy and congestive heart failure –> dyspnoea, hepatomegaly, bilateral lower extremity, presacral oedema
  • Neuro:
    • Sensory usually bilateral and symmetrical
    • Autonomic: postural hypotension, impotence, GIT motility disturbance
  • GIT:
    • Hepatomegaly: amyloid infiltration or CHF
26
Q

Primary systemic amyloidosis - where to biopsy

A
  • 80-90% of patients will have amyloid deposits in the rectal mucosa or in abdominal subcutaneous fat –> abdominal subcutaneous fat is better as the former has a higher risk of bleeding
  • Gingival and tongue biopsies may also be obtained to demonstrate the presence of amyloid
  • Bone marrow biopsies: examined for presence of amyloid deposits
  • Most of these are amyloid P: you can do ?? scintigraphy on this, and is quite sensitive for locating amyloid deposits
  • More practical method: measurement of serum free light chains
27
Q

Primary systemic amyloidosis histology

A
  • Amyloid deposits in the dermis and subcutis
  • Rarely around the sweat glands, and within blood vessel walls
  • Rarely, specific infiltrates of amyloid-producing plasma cells can be found adjacent to amyloid deposits
28
Q

Investigations for primary systemic amyloidosis

A
  • Blood: serum EPG, IEPG, free light chains
  • Urine: EPG and IEPG
  • Bone marrow aspirate - Congo red stain
  • Directed organ involvement:
    • Renal: UEC, urine, LFT
    • Cardiac: BNP, trpononin, TTE, MRI
    • Nerve conduction studies
    • Amyloid P scintiography
29
Q

Primary systemic amyloidosis treatment

A
  • Poor prognosis: ~13 months, particularly if cardiac involvement
  • Treatment similar to multiple myeloma: melphalan and systemic steroids
  • Younger patients with minimal cardiac involvement: high dose melphalan and autologous peripheral blood stem cell transplantation –> 8 year follow up had complete response in 40% of patients, survival benefit also seen for those without complete response
  • Older with cardiac involvement: newer targeted agents - lenalidomide, pomalidomide, bortezomib, daratumumab
  • Supportive measures - i.e. nephrotic syndrome requires diuretic treatment
30
Q

Secondary systemic amyloidosis

A
  • complication of severe chronic inflammatory diseases of infectious or non-infectious
  • Eg: TB, lepromatous leprosy, RA, ankylosing spondylitis, dystrophic EB, HS, etc
  • Deposition of distinctive non-immunoglobulin protein AA –> precursor is an acute phase protein which is synthesized by the liver, appears to have a regulatory function in lipoprotein metabolism during inflammation
  • AA amyloidosis usually affects the kidneys, liver, spleen, adrenals and heart
  • Cutaneous lesions are rarely seen, but you can detect in in fat aspirates
  • If treat underlying disease, can halt the progression
  • Eprodisate may slow the loss of renal function in AA amyloidosis
31
Q

Haemodialysis associated amyloidosis

A
  • From decreased excretion of beta-2 microglobulin –> retained within circulation and has tendency to deposit in synovial membranes
  • Long-term haemodialysis for renal failure
  • Cutaneous: MSK: carpal tunnel syndrome, bone cysts, destructive spondyloarthropathy
  • Rarely subcutaneous nodules
32
Q

Inherited amyloidoses

A 
Familial finnish type
Muckle-Wells
FMF
Sipple syndrome or MEN type 2a
Hypotrichosis simplex of the scalp
X-linked pigmentary disorder

Derm (57 decks)

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