common dermatoses in dermatology Out patient department.

1. CUTANEOUS AMYLOIDOSIS
Dr Kamal jung shahi
1st year Resident
Dermatology (NGMC-TH)

2. Introduction
• Amyloid-`Starch like´ (latin amylum)
• Term introduced by Rudolf Virchow
• Extracellular precipitates that turns brown after incubation
with iodine.
• Amyloid proteins show a highly conserved antiparallel β‐sheet
conformation and form non‐branching linear fibrils of variable
lengths, with diameters of 7.5–10 nm.

3. Introduction
• Amyloidosis- abnormal deposition of amyloid
• Deposition can occur as a skin skin-limited disorder
– Primary localized cutaneous amyloidosis
– Secondary localized cutaneous amyloidosis
• Manifestation of systemic amyloidosis
– Most common- immunoglobulin light chain
amyloidosis(AL).

4. Classification:
A. Localized cutaneous:
• Amyloid precipitates located to skin
• Mostly limited to the papillary dermis
• Differentiated into two types-
1) Hereditary type(familial PLCA):- A Apo-E4, papular lesion.
2) Non-hereditary localized cutaneous amyloidosis:
o Primary localized cutaneous amyloidosis(PLCA)
I. Papular PLCA(AK)
II. Macular PLCA(AK)
III. Nodular PLCA(Al)
o Secondary localized cutaneous amyloidosis(predominantly AK)

5. B. Systemic amyloidosis with cutaneous
involvement
1. Non‐hereditary systemic amyloidoses with
cutaneous involvement.
a) Primary systemic and myeloma or plasmocytoma‐associated
amyloidosis (AL)
b) Secondary systemic amyloidosis associated with
inflammation/ tumour (AA)
c) Secondary haemodialysis associated systemic amyloidosis
(Aβ2M).

6. 2. Hereditary systemic amyloidoses with
cutaneous involvement:
a) Hereditary transthyretin amyloidosis/familial amyloid
polyneuropathy (ATTR).
b) Hereditary ApoA1 amyloidosis (AApoA1)
c) Hereditary cystatin C amyloidosis (ACys)
d) Hereditary gelsolin amyloidosis (Meretoja syndrome) (AGel)
3. Hereditary systemic diseases with secondary
cutaneous amyloidosis
a) Muckle–Wells syndrome (AA)
b) TNF receptor 1 associated periodic fever syndrome (TRAPS)
(AA)

7. Epidemiology
• Incidence and prevalance
– Macular(35%)
– Papular(35%)
– Mixed/biphasic/allotropic(15%)
– Nodular /tumefactive(1.5%)
• Sex
– Women more frequently affected(F:M-2-3:1)
Ethnicity: In Asia, papular PLCA (c . 75%) is far more frequent
than macular PLCA (c . 10%). Interestingly, mixed
maculopapular PLCA is more frequent (15%) in Asia than the
macular type.

8. Pathophysiology
Papular and Macular PLCA
• Amyloid K is key feature of localized cutaneous amyloidosis
• Friction plays major role as mechanical stimulus
induces apoptosis of basal keratinocytes lead to increased
cytokeratin release.
Apoptotic basal keratinocytes release cytokeratin
Covered with autoantibodies
Partially Phagocytosed by macrophage and enzymatically degraded to amyloid K(cytokeratin)

9. Nodular PLCA:
• Plasma cells infiltrating the skin (e.g. in
extramedullary plasmocytoma) produce monoclonal
immunoglobulin light chains of κ‐ or λ‐type as
amyloid precursors.
• Another difference is , nodular PLCA infiltrates the
entire dermis, from the papillary dermis to the
subcutis.

10. Cutaneous amyloidoses due to systemic disease
A. Most non‐hereditary primary systemic amyloidoses are caused by
monoclonal plasma cell proliferation
• Associated with multiple myeloma, Waldenström disease, Bence Jones
plasmocytoma, heavy chain disease, malignant lymphomas and others.
• Mostly immunoglobulin light chains (isotypes κ and λ) serve as amyloid
prescursors in ratio 1:2.
• Reason for dermatorrhagia are that factor X is decreased by binding to
amyloid fibrils, and that amyloid deposits in the blood vessel walls
increase vessel wall fragility.
• A myloid precipitation within the oral cavity mucosa may present as
papules in a local deposition or as macroglossia in a diffuse infiltration.

11. B. In secondary systemic amyloidoses, a specific underlying
disease leads to the deposition of amyloid in different tissues.
• Most common being AA type.
• Chronic inflammation (infectious or non‐infectious) or neoplastic
diseases, as well as sporadic gene defects, lead to enhanced
production of SAA, an acute phase protein.
• Hepatic production of SAA is stimulated by IL‐1 (among others),
and macrophages degrade SAA to amyloid A.
• Interestingly, experimental cutaneous amyloidosis due to
Leishmania infection has been described.
• Another variant of secondary systemic amyloidosis with
cutaneous involvement occurs in haemodialysis patients with β2
‐microglobulin (β‐sheet structure) as the amyloid precursor.

12. AMYLOIDOSIS: PATHOPHYSIOLOGY
• The amyloidogenic precursors may
trigger amyloid formation when
their concentration ↑es in serum or
because a mutation favors
misfolding.
• Interaction with the extracellular
environment may result in
incomplete proteolytic cleavage
and binding to matrix components
such as glycosaminoglycans
(GAGs) and collagen that facilitate
aggregation.
• Serum amyloid P (SAP) binds to
amyloid fibrils and protects them
from reabsorption via normal
protein scavenging mechanisms.

13. Papular PLCA
• Also known as Lichenoid PLCA , Lichen amyloidosus.
• Firm papules with pink to brownish lichenoid
glossiness.
• Distribution: lower leg, forearm, trunk
• D/D : LSC, Hypertrophic LP
• Variants:
i. Mixed (syn. biphasic or allotropic) PLCA (= papular
and macular),
ii. Poikilodermatous variant (= lichenoid papules,
blisters, poikilodermatous lesions)

14. Lichenoid primary localized cutaneous amyloidosis on the ankle of a male patient

15. Biphasic amyloidosis. Characteristic rippled hyperpigmentation of
macular amyloidosis (superiorly) as well as papules of lichenoid amyloidosis
(inferiorly)

16. Lichen amyloidosis. Keratotic, hyperpigmented
plaques on the legs

17. Macular PLCA
• Also k/a : Friction or, Brush amyloidosis
• well or vaguely demarcated, hyperpigmented, yellowish to
brownish macules.
• Associated with areas of friction.
• Amyloid precursor is Cytokeratin (predominantly cytokeratin
5).
• Distribution: interscapular region, extremities, trunk.
• D/D: Atopic eczema,PIH, LSC, fixed drug eruption,
atrophoderma of Pasini and Pierini, anetoderma, morphoea
• Associations:
o MEN2a, primary biliarycirrhosis

18. • Variants:
i. Mixed (syn. biphasic or allotropic) PLCA (= papular and
macular)
ii. Poikilodermatous PLCA (macules, blisters, poikilodermatous
lesions),
iii. Amyloidosis cutis dyschromica ( mottled hyper‐ and
hypopigmented macules)
iv. Anosacral PLCA (predominantly in Japan).

19. Macular primary localized cutaneous amyloidosis. Macular cutaneous
amyloidosis on the chest

20. Nodular PLCA
• Also k/a : Tumefactive (swelling)
• solitary or multiple, mostly asymptomatic,
brownish to red, firm plaques or nodules.
• Distribution: feet, nose, genitals, legs, head
• D/D :
i. Naevus lipomatosus,
ii. Cutaneous lymphomas
• Associations: paraproteinaemia, diabetes,
Sjogren syndrome, CREST syndrome.

21. Nodular (tumefactive) primary localized cutaneous amyloidosis

22. Nodular (tumefactive) primary localized cutaneous amyloidosis

23. Nodular amyloidosis

24. Primary systemic amyloidoses(AL)
• Manifestation of underlying plasma cells dyscrasia
– Myeloma or
– Plasmacytoma associated
• Amyloid fibril precursor: immunoglobin light chains usually λ-type
(75–80%).
Cutaneous findings:
• Petechiae,Haemorrhages
• Nail dystrophy
• Waxy papules/nodules/plaques
• Tumorous lesions
• Scleroderma like infiltration
• Bullous lesions
• Alopecia and Cutis laxa.

25. Purpura and yellow brown plaque
in periorbital distribution Macroglossia with dental impression
On the tongue
Papulonodules of tongue
Numerous waxy translucent facial papule

26. Plasmacytoma‐associated systemic amyloidosis with cutaneous involvement: in
the submammary region and in the inguinal region

27. Primary systemic amyloidosis
with cutaneous involvement
showing prominent periorbital
bleeding
Haemorrhagic bulla
in primary systemic
amyloidosis
Nail dystrophy

29. • Clinically evident skin involvement: nearly 25% of individual.
• Extra-cutaneous Findings:
 Macroglossia,
 Nephropathy,
 Cardiomyopathy, neuropathy, intestinal involvement, carpel
tunnel syndrome.
• Associations: acquired von Willebrand syndrome.
• Variants:
1. bullous amyloidosis,
2. oral mucosal bullous amyloidosis

30. Secondary systemic amyloidosis
• Complication of severe chronic inflammatory diseases of an
infectious or non-infectious nature- Tuberculosis,Lepromatous
leprosy,Rheumatoid arthritis,Ankylosing spondylitis .
• Deposition of a distinctive non-immunoglobulin protein designated
AA (amyloid A protein)
• Precursor –
– Acute phase protein(SAA)
– Synthesized by the liver
– Regulatory function in lipoprotein metabolism during inflammation
• AA amyloidosis usually affects the kidneys, liver, spleen, adrenals,
and heart

31. • Cutaneous findings
– Minor cutaneous involvement sometimes
petechiae,purpura and alopecia.
• Extracutaneous findings
– Nephropathy
– Hepatosplenomegaly
– Gastrointestinal disorders
• Bleeding
• Motility disorders

32. Secondary Hemodialysis-Associated Amyloidosis
• Decreased excretion of β2-Microglobulin
• Patients receiving long-term hemodialysis for renal failure.
• β2-microglobulin is not readily filtered through dialysis
membranes,
– Retained within the circulation.
– Tendency to deposit in synovial membranes.
– Commonly present as Soft plaques.
– Musculoskeletal manifestations ;
• Carpal tunnel syndrome,
• Bone cysts
• Destructive spondyloarthropathy
• Skin lesions- subcutaneous nodules,soft plaques
• Associated with diabetes mellitus and nephropathy.

33. Hereditary systemic amyloidoses with
cutaneous involvement
1. Hereditary transthyretin amyloidosis/familial amyloid polyneuropathy
(ATTR)
• Most common
• Deposition of altered transthyretin (a protein of the prealbumin fraction)
• Associated with Val30Met mutation
• Cutaneous findings-
– Atrophic scars
– Non-healing ulcers
– Petechiae

34. 2. Hereditary gelsolin amyloidosis
• Meretoja syndrome
• Deposition of amyloid gelsolin
• Cutaneous findings
– Cutis laxa
– Pruritus
– Petechiae, Ecchymoses
– Hypotrichosis, alopecia
• Extracutaneous findings
– Corneal dystrophy
– Neuropathy often with cranial nerve involvement,
– CTS(carpel tunnel syndrome)
– Minor nephropathies

35. Muckle-Wells-syndrome
• Rare syndrome
• Serum amyloid-A (SAA) deposition.
• Cutaneous findings shows; Cold sensitivity,
pruritus, cold urticaria like lesions.
• Familial urticaria during early childhood
• Periodic attacks of Fever, chills, arthralgia,
leukocytosis, lancinating limb pain
• Progressive perceptive deafness over time.
• May be an associated AA amyloid nephropathy

36. TNF receptor 1 associated periodic fever
syndrome(TRAPS)
• Deposition of amyloid SAA
• Associated with Mutations of extracellular domain of TNF receptor 1
• Cutaneous findings
– Periorbital oedema
– Migrating cutaneous erythemas
– Conjunctivitis
• Extracutaneous findings
– Prolonged episodic fever period
– Abdominal pain
– Myalgia

37. Investigations:

38. Histologic Criteria for the Definition of Amyloid
■ Homogenous-hyaline
■ Mostly extracellular
■ Typical 10 to 15 nm fibrils by electron microscopy
■ Metachromasia
■ Congo red birefringence
■ Thioflavin T yellow-green fluorescence
■ Multiple chemical types

39. Histologic features of amyloid deposits within the
skin. The dermal deposits are eosinophilic,
amorphous and contain fissures (arrow) By
electron microscopy, there are clusters of
filamentous deposits (*) and 7–10-nm non-
branching fibrils (inset)

40. Fig: congo red stain; Dermal diffuse deposit of amyloid
observed under polarized light showing ‘‘apple-green’’
birefringence, in contrast to the white birefringence of
the adjacent collagen bandles.

41. Use of special stains to identify amyloid deposits within the papillary dermis in lichen
amyloidosis. A. With a Congo red stain, there is characteristic green birefringence with
polarized light; the color can vary from yellow–green to blue–green B. With a Thioflavin
T stain, amyloid deposits stain brightly with ultraviolet fluorescence microscopy C
Positive immunohistochemical stain for keratin .

42. Treatment
• Multidiciplinary approach should be undertaken
• Pruritus is major problem in all types of
cutaneous amyloidoses
• Antipruritic treatment should be one component
of treatment regimen
• Systemic amyloidoses- treatment of underlying
disease has highest priority

43. Treatment options
• Potent topical corticosteroids alone or combined with
keratolytics
• Protect from scratching by applying occlusive dressings
such as hydrocolloids or gauze wraps impregnated with zinc
oxide for a period of weeks to months.
• Topical calcineurin inhibitors may play an adjunctive role
• Dermabrasion was shown to be beneficial in lichen
amyloidosis involving the limbs with the effects lasting at
least five years
• CO2 or erbium:YAG laser therapy has also been shown to
be of benefit in some patients with macular and lichen
amyloidosis

44. • Acitretin (0.5 mg/kg/day) has been reported to
improve pruritus and result in flattening of
lesions, with some clearance of the associated
hyperpigmentation.
• Low-dose cyclophosphamide (one study
reporting on significantly reduced pruritus,
hyperpigmentation and lesion size after 50 mg
per day oral cyclophosphamide over 6 months.)
• Surgical excision, cryotherapy, electrodesiccation,
and CO2 laser can be used to treat nodular
amyloidosis, but local recurrences are common

45. Treatment of Macular and Lichen amyloidoses

46. Systemic amyloidoses
• Immunosuppression- treatment of amyloidoses
secondary to inflammation
• Familial mediterranean fever induced AA amyloidosis-
– Colchicine
– Anakinra(IL-1 receptor antagonist)
• TRAPS associated amyloidosis
– TNF blockade
– IL-1 antagonists

47. • Muckle–Wells syndrome
Treatment options include
– Canakinumab (IL‐1β anti- body),
– Rilonacept (IL‐1‐binding protein) and
– Anakinra (IL‐1Ra)

48. Thank You