Cutaneous Amyloidosis — 10-Marks Format (3rd Year Dermatology)

DEFINITION

1. Primary (localised) cutaneous amyloidosis — amyloid confined to skin, no internal organ involvement
2. Cutaneous manifestations of systemic amyloidosis — skin involvement secondary to underlying systemic disease

PART 1: PRIMARY LOCALISED CUTANEOUS AMYLOIDOSIS (PLCA)

Classification

1. Macular Amyloidosis

• Epidemiology: Women > men (5:1); common in Asian, Hispanic, Middle Eastern populations; presents in early adulthood
• Pathogenesis: Repeated friction (nylon brushes, abrasive bathing) → traumatic damage to basal keratinocytes → keratin (K5) deposits as amyloid in dermal papillae
• Clinical features:
  • Pruritic (may be asymptomatic) brown-gray macules with a characteristic rippled or "salt-and-pepper" pattern, best seen on stretching the skin
  • Primarily interscapular region of back (over scapulae); also extensor extremities, thighs, breasts, buttocks
  • A linear or nevoid distribution is occasionally seen
• Association: Notalgia paresthetica (pruritus of scapular region → repeated scratching → macular amyloid)

2. Lichen Amyloidosis

• Epidemiology: Most common form of PLCA; men > women (2:1); middle-aged adults
• Pathogenesis: Same friction-induced keratinocyte damage as macular amyloidosis; the two represent ends of a clinical spectrum
• Clinical features:
  • Intensely pruritic, discrete, firm, brown scaly papules that coalesce into verrucous plaques
  • Classic site: bilateral shins (extensor surfaces); also anterior thighs, forearms
  • Rippled or ridged pattern of plaques; initially unilateral, becomes bilateral over time
  • An anosacral variant with lichenification of anal and sacral regions is described
• Association: ~1/3 of patients with MEN-2A (multiple endocrine neoplasia type 2A) have lichen amyloidosis; macular amyloidosis of early onset (<20 years) must trigger screening for MEN-2A (check RET mutation, serum calcitonin, thyroid palpation, BP for phaeochromocytoma)

3. Nodular Amyloidosis

• Epidemiology: Rare; older adults; females predominate
• Pathogenesis: Amyloid is AL (immunoglobulin light chains) — produced by local plasma cell infiltrate, NOT keratin-derived
• Clinical features:
  • Single or multiple, asymptomatic, skin-coloured or yellowish nodules/tumefactions
  • Preferentially acral areas (fingers, toes); also trunk, face, genitalia
  • Overlying epidermis may appear atrophic; lesions may resemble bullae
• Important: ~7% progress to systemic AL amyloidosis → regular follow-up mandatory
• Associations: Sjögren syndrome, systemic sclerosis (CREST), rheumatoid arthritis; may represent early MALT lymphoma (plasma cell infiltrate)

4. Biphasic Amyloidosis

• Fine papular lesions superimposed on a background of macular hyperpigmentation
• Represents coexistence of both forms; same keratin-derived pathogenesis

5. Familial/Hereditary Forms

• Familial Primary Localised Cutaneous Amyloidosis (FPLCA): Autosomal dominant; mutations in OSMR (oncostatin M receptor β) or IL-31RA genes → IL-31 signalling defect → impaired MCP-1 secretion → keratin debris accumulates → amyloid. Onset 5–18 years; widespread lesions on limbs, back, chest
• Amyloidosis cutis dyschromica: Subset of FPLCA; childhood onset, no pruritus; dotted reticular hyperpigmentation with hypopigmented spots over most of body; common in Japan, Taiwan, India
• MEN-2A-associated: Macular/lichen amyloidosis on upper back; mutation in RET proto-oncogene

6. Secondary Cutaneous Amyloidosis

Histopathology of PLCA

• Dermal papillae expanded by amorphous, eosinophilic, homogeneous deposits in H&E
• Deposits sit immediately sub-epidermal (unlike systemic — no perivascular deposits)
• Overlying epidermis: hyperkeratosis, acanthosis; focal necrotic basal keratinocytes
• Melanin classically present within amyloid (explains hyperpigmentation)
• Special stains:
  • Crystal violet → metachromasia
  • Alkaline Congo red → salmon-pink staining
  • Congo red under polarised light → apple-green birefringence (pathognomonic)
  • Electron microscopy → 7–10 nm non-branching fibrils
• Immunoperoxidase for keratin confirms primary cutaneous amyloid (keratin-derived)
• DIF: IgM globular deposits (passive absorption, not specific)

Treatment of Macular/Lichen Amyloidosis

PART 2: CUTANEOUS MANIFESTATIONS OF SYSTEMIC AMYLOIDOSIS

Overview

A. Primary Systemic AL Amyloidosis (Most Clinically Important)

1. Macroglossia — uniformly enlarged, firm tongue (pathognomonic when present); may show haemorrhagic papules/plaques/blisters; xerostomia from salivary gland infiltration; rubbery intraoral swellings
2. Pinch purpura / periorbital purpura ("raccoon eyes" sign):
   • Petechiae, purpura, ecchymoses after minor trauma — due to amyloid infiltration of vessel walls making them fragile
   • Characteristic sites: eyelids, neck, axillae, anogenital region
   • Precipitated by: coughing, Valsalva manoeuvre, proctoscopy, rubbing skin, even adhesive tape removal
3. Waxy papules, nodules, and plaques:
   • Smooth, waxy, translucent or purpuric papules a few mm in diameter
   • Sites: face, neck, scalp, anogenital region, eyelids
   • Smooth erythematous waxy infiltration of palms and volar fingertips
4. Sclerodermoid/infiltrative skin changes — diffuse cutaneous infiltration → scleroderma-like thickening
5. Cutis verticis gyrata with alopecia — scalp skin thrown into folds resembling cutis verticis gyrata from diffuse scalp infiltration
6. Nail changes — longitudinal ridging and thinning resembling lichen planus; amyloid deposits around nail vessels and in nail bed/matrix dermis
7. Bullous lesions — haemorrhagic blisters resembling porphyria cutanea tarda or epidermolysis bullosa acquisita; may be initial presentation
8. Acquired acral cutis laxa — rarely

B. Secondary Systemic AA Amyloidosis

• Caused by serum amyloid A protein (SAA) — an acute-phase reactant deposited in chronic inflammatory diseases (RA, juvenile idiopathic arthritis, IBD, familial Mediterranean fever, chronic infections)
• Cutaneous involvement is uncommon; when present, similar waxy papules and purpura may be seen
• Primarily involves kidneys (nephrotic syndrome), liver, spleen
• Note: Eprodisate (alters amyloid conformation) may slow renal decline

C. Haemodialysis-Associated Amyloidosis (Aβ2M)

• Amyloid from β2-microglobulin (not excreted by dialysis membranes)
• Primarily musculoskeletal (carpal tunnel syndrome, bone cysts, spondyloarthropathy)
• Skin involvement: occasional subcutaneous nodules
• Incidence declining with improved high-flux dialysis membranes

D. Inherited (Heredofamilial) Systemic Amyloidoses

• Transthyretin amyloidosis (ATTRv): Most common inherited systemic amyloidosis; mutations in TTR gene; cardiac or neurologic predominance; skin rarely involved but fat pad biopsy positive early; treatment: tafamidis (TTR stabiliser), patisiran (siRNA), inotersen (antisense oligonucleotide), liver transplant
• Familial amyloidosis, Finnish type (AGel amyloidosis): Gelsolin gene mutation; triad of corneal lattice dystrophy + cranial neuropathies + cutis laxa-like skin changes + skin fragility

Summary Table: Key Distinguishing Points

Approach to an Adult Patient with Hair Loss

10-Marks Format — 3rd Year Dermatology PG Theory

INTRODUCTION

I. HISTORY (Key Points)

A. Nature of Hair Loss

• Shedding vs. hair breakage — shedding implies follicular/systemic disease; breakage suggests shaft defect or trauma
• Shedding vs. only reduction in density — density reduction without shedding points to hair follicle miniaturisation (AGA)
• Pattern: diffuse, patterned (frontal, vertex), or patchy
• Expected hair length — "hair that never grows long" suggests anagen defect

B. Temporal Profile

• Duration and age of onset
• Persistent vs. intermittent (recurrent episodes suggest alopecia areata)
• Rate of progression — rapid loss within weeks vs. slow thinning over years

C. Scalp Symptoms

• Pruritus, burning, trichodynia (pain/paresthesias of scalp) — common in lichen planopilaris, active AGA
• Tenderness, pustules, drainage — suggestive of folliculitis decalvans, dissecting cellulitis

D. Triggering Factors (for telogen effluvium)

• Postpartum (2–4 months after delivery)
• Febrile illness, major surgery, crash dieting, severe emotional stress (~3 months prior)
• Medications: anticoagulants, anti-thyroid drugs, retinoids, chemotherapy, antidepressants, OCP withdrawal, lithium
• Nutritional deficiency: iron, zinc, biotin, protein
• Flare of systemic disease (SLE, IBD)
• SARS-CoV-2 infection (telogen effluvium in ~25% within 2 months)

E. Systemic Review

• Thyroid symptoms (hypothyroidism → diffuse effluvium; hyperthyroidism → thin brittle hair)
• Menstrual irregularity, hirsutism, acne → polycystic ovarian syndrome / hyperandrogenism
• Weight loss, fatigue, pallor → malignancy, iron deficiency anaemia
• Nail changes, joint pains → connective tissue disease

F. Family History

• AGA is polygenic; ~25% of alopecia areata patients have a positive family history
• Familial primary localised cutaneous amyloidosis (FPLCA) — autosomal dominant

G. Treatment History

• Previous therapies, duration, compliance
• Current medications and supplements (biotin interferes with avidin-based lab tests)
• Hair styling practices: tight braids (traction alopecia), chemical relaxers, heat styling

II. PHYSICAL EXAMINATION

A. General Examination

• Signs of hyperandrogenism: hirsutism, acne, clitoromegaly
• Thyroid enlargement
• Body habitus, nutritional status
• Nails: pitting (alopecia areata), ridging (lichen planopilaris-like changes in AL amyloidosis)
• Eyebrows/eyelashes: absent lateral eyebrow → frontal fibrosing alopecia (FFA), hypothyroidism

B. Scalp Examination — The Critical Step

• Perifollicular erythema and scale (keratosis) at margin → lichen planopilaris
• "Exclamation point" hairs (tapered proximally) → alopecia areata
• Pustules at hair-bearing margin → folliculitis decalvans
• Broken hairs at different lengths, angular/geometric pattern → trichotillomania

III. DIAGNOSTIC TESTS

1. Hair Pull Test (Gentle Traction Test)

• Grasp 50–60 hairs between thumb and forefinger; gentle traction applied
• Positive: >6 hairs extracted (>10% of grasped hairs) = active shedding
• Positive in: active telogen effluvium, active alopecia areata, active lichen planopilaris
• Proximal end of extracted hairs examined (club-shaped telogen root vs. dystrophic anagen root)

2. Trichoscopy (Dermoscopy of Hair and Scalp)

3. Hair Card Test (Window Test)

• Hairs laid over a white card; assess shaft thickness, pigmentation, and uniformity

4. Trichogram (Epiluminescence Trichogram)

• 50–80 hairs forcefully epilated from specific scalp sites
• Examined microscopically for anagen:telogen ratio
• Normal: anagen 80–90%, telogen 10–15%
• Telogen effluvium: >25% telogen hairs
• Alopecia areata: dystrophic anagen hairs

5. Light Microscopy of Hair Shafts

• Polarised light useful for structural hair shaft defects (trichorrhexis nodosa, pili torti, monilethrix)

6. Wood's Lamp Examination + Fungal Culture (Scalp Scraping/Hair Pluck)

• Tinea capitis: Microsporum sp. — bright green fluorescence; Trichophyton sp. — no fluorescence
• Culture on Sabouraud's medium essential for species identification

7. Scalp Biopsy (Trichoscopy-Guided)

• Indication: Suspected cicatricial alopecia, unclear diagnosis, before initiating aggressive therapy
• Technique: 4 mm punch at the hair-bearing active margin (not central burnt-out zone)
• Two biopsies preferred: one for vertical sectioning (architecture), one for horizontal sectioning (follicular density, T:V ratio)
• DIF biopsy if discoid lupus erythematosus (DLE) or lichen planopilaris/mucous membrane pemphigoid suspected
• Extend into subcutaneous fat

8. Blood Tests (Directed by History and Examination)

• All cases of diffuse loss: TSH (hypothyroidism), serum ferritin and iron studies, CBC (anaemia)
• Women with pattern loss / suspected hyperandrogenism: Total and free testosterone, DHEA-S, 17-hydroxyprogesterone, LH:FSH ratio, prolactin
• Suspected SLE/connective tissue disease: ANA, anti-dsDNA, complement
• Telogen effluvium: Iron, thyroid, renal/liver function, zinc
• Nutritional deficiency: Zinc, Vitamin D, Vitamin B12, folate
• Note: Biotin supplementation (common in patients with hair loss) interferes with avidin-based immunoassay laboratory tests

IV. CLASSIFICATION OF ALOPECIA (Diagnostic Framework)

ALOPECIA
├── NON-SCARRING (follicular ostia preserved)
│   ├── Diffuse
│   │   ├── Telogen effluvium (acute/chronic)
│   │   ├── Anagen effluvium (chemotherapy)
│   │   └── Diffuse alopecia areata
│   ├── Patterned
│   │   ├── AGA — Male (Hamilton-Norwood I–VII)
│   │   └── AGA — Female (Ludwig I–III / Sinclair I–V)
│   └── Patchy/Circumscribed
│       ├── Alopecia areata (+ totalis, universalis, ophiasis)
│       ├── Tinea capitis
│       ├── Secondary syphilis ("moth-eaten")
│       ├── Traction alopecia
│       └── Trichotillomania
└── SCARRING (cicatricial) — follicular ostia absent
    ├── Primary Cicatricial (follicle is target)
    │   ├── Lymphocytic: LPP, FFA, DLE, CCCA
    │   └── Neutrophilic: Folliculitis decalvans, Dissecting cellulitis
    └── Secondary Cicatricial (follicle bystander)
        ├── Burns, radiation, morphea
        └── Cutaneous malignancies, sarcoidosis, NL

V. COMMON DIAGNOSES — DISTINGUISHING FEATURES

VI. MANAGEMENT PRINCIPLES

Non-Scarring — Reversible

1. AGA:
   • Males: Finasteride 1 mg/day (5α-reductase inhibitor); topical minoxidil 5% solution/foam BD; low-dose oral minoxidil 0.25–1.25 mg/day
   • Females: Topical minoxidil 2–5%; oral minoxidil (low dose); spironolactone; finasteride (post-menopausal)
   • Adjuncts: PRP (platelet-rich plasma), low-level laser therapy, hair transplantation
2. Telogen effluvium: Identify and treat the trigger; iron, thyroid correction; reassurance (spontaneously resolves in 6 months)
3. Alopecia areata:
   • Limited (<50%): Intralesional triamcinolone acetonide (5–10 mg/mL); potent topical steroids
   • Extensive (>50%): Oral prednisolone pulse; contact immunotherapy (DPCP/SADBE); Jak inhibitors (baricitinib, ritlecitinib — FDA approved); PUVA
   • Topical minoxidil as adjunct

Scarring — Irreversible (Halt Progression)

• LPP/FFA: Hydroxychloroquine; topical/intralesional steroids; doxycycline; pioglitazone; dutasteride (FFA)
• Folliculitis decalvans: Rifampicin + clindamycin combination; dapsone
• DLE: Potent topical steroids, antimalarials (hydroxychloroquine), systemic retinoids
• Dissecting cellulitis: Dapsone, rifampicin, isotretinoin, biologics; surgical drainage

General Advice

• Address psychological burden and quality-of-life impact
• Camouflage techniques and trichopigmentation for cicatricial cases
• Discuss realistic expectations: halting progression vs. regrowth
• Pregnancy plans before prescribing finasteride/dutasteride (teratogenic — Category X)

SUMMARY FLOWCHART

Adult with hair loss
        ↓
Is there scarring? (Follicular ostia absent?)
    YES → Cicatricial alopecia → URGENT → Biopsy → Classify → Halt inflammation
    NO  → Non-cicatricial
              ↓
         Diffuse?          Patchy?          Patterned?
            ↓                 ↓                 ↓
    Telogen effluvium   Alopecia areata    AGA (M or F)
    Anagen effluvium    Tinea capitis      Traction
    Thyroid/iron/SLE    Secondary syphilis  FFA
            ↓
    History + Trichoscopy + Trichogram + Blood tests → Diagnosis → Treat cause