Cutaneous amyloidosis by dermatology resident.pptx

common dermatoses in dermatology Out patient department.

1. CUTANEOUS AMYLOIDOSIS Dr K amal jung shahi 1 st 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: Localized cutaneous: Amyloid precipitates located to skin Mostly limited to the papillary dermis Differentiated into two types- Hereditary type(familial PLCA ):- A Apo-E4, papular lesion. Non-hereditary localized cutaneous amyloidosis: Primary localized cutaneous amyloidosis(PLCA) Papular PLCA(AK) Macular PLCA(AK) Nodular PLCA(Al) Secondary localized cutaneous amyloidosis(predominantly AK)

5. B. Systemic amyloidosis with cutaneous involvement Non‐hereditary systemic amyloidoses with cutaneous involvement. Primary systemic and myeloma or plasmocytoma ‐associated amyloidosis (AL) Secondary systemic amyloidosis associated with inflammation/ tumour (AA) Secondary haemodialysis associated systemic amyloidosis (A β2 M).

6. 2. Hereditary systemic amyloidoses with cutaneous involvement: Hereditary transthyretin amyloidosis/familial amyloid polyneuropathy (ATTR). Hereditary ApoA1 amyloidosis (AApoA1) Hereditary cystatin C amyloidosis ( ACys ) Hereditary gelsolin amyloidosis ( Meretoja syndrome) ( AGel ) 3. Hereditary systemic diseases with secondary cutaneous amyloidosis Muckle –Wells syndrome (AA) 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 autoantibodie s 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 L ichenoid PLCA , L ichen amyloidosus . Firm papules with pink to brownish lichenoid glossiness. Distribution: lower leg, forearm, trunk D/D : LSC, Hypertrophic LP Variants : Mixed (syn. biphasic or allotropic) PLCA (= papular and macular), P oikilodermatous 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: MEN2a , primary biliary cirrhosis

18. Variants: Mixed (syn. biphasic or allotropic) PLCA (= papular and macular) P oikilodermatous PLCA ( macules , blisters , poikilodermatous lesions ), Amyloidosis cutis dyschromica ( mottled hyper‐ and hypopigmented macules ) A nosacral 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 : Naevus lipomatosus, 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

28. Clinically evident skin involvement: nearly 25% of individual. Extra-cutaneous Findings: Macroglossia , N ephropathy, C ardiomyopathy, neuropathy, intestinal involvement, carpel tunnel syndrome. Associations : acquired von Willebrand syndrome. Variants: bullous amyloidosis, oral mucosal bullous amyloidosis

29. 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

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

31. 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.

32. 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

33. 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

34. 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

35. 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

36. Investigations:

37. 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

38. 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)

39. 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 .

40. 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 .

41. 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

42. 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

43. 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

44. Treatment of Macular and Lichen amyloidoses

45. 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

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

47. Thank You