Amyloidosis systemic (overview) E85.9

Virchow 1858; Wild 1886; Lubarsch 1923; Pick 1931;

Amyloidoses are rare protein folding diseases in which proteins are deposited as insoluble fibrillar aggregates as a result of a conformational change.

Systemic amyloidoses are differentiated into:

• primary systemic amyloidoses.
• secondary (reactive) systemic amyloidoses.

Another classification distinguishes between:

• acquired systemic (generalized) amyloidoses (95% of all systemic amyloidoses).
• hereditary or familial systemic amyloidoses

Systemic amyloidoses must be separated from localized (non-systemic) amyloidoses.

Amyloidoses systemic (rare; unlike non-systemic cutaneous amyloidoses, they have little dermatologic relevance):

• Hereditary amyloidoses (rare; 5% of all cases).
  • AATR (mutated transthyretin)
    • FAP (familial amyloid polyneuropathy)
    • FAC (familialcardiomyopathy)
  • Other very rare hereditary amyloidoses
    • AFib (fibrinogen aalpha)
    • ALys(lysozyme)
    • AGel(gelsolin)
    • ACys(cystatin C)
• Acquired systemic (generalized) amyloidoses (95% of all cases)
  • AL- or AH-type amyloidosis (immunoglobulin type - L stands for light chain, H stands for heavy chain)
    • Gammopathy-associated amyloidosis
    • Myeloma-associated amyloidosis.
  • AA-type amyloidosis (serum amyloid A):
    • Amyloidoses associated with chronic inflammation; increased formation of acute-phase serum amyloid A protein associated with inflammation (rheumatoid arthritis, inflammatory bowel disease, syphilis, leprosy, tuberculosis, cystic fibrosis).
    • AApoA-IVAmyloidosis with nephrogenic and cardiac involvement pattern
  • Microglobulin associated amyloidosis-ß2
    • Amyloidosis associated with long-term dialysis(beta-2 microglobulin deposition); long-term dialysis leads to accumulation of A-ß2 as it is not dialyzed with. Organ: Joints, skin; tendons and tendon attachments.

    • Amyloid type (AE): Amyloid formed during the production of endocrine hormones. Occurrence: diabetes mellitus, medullary thyroid CA; organs: heart, kidneys, glandular tissue, lungs, skin.

    • Amyloid type (AS):Various proteins deposited in organs during aging process. Occurrence: senile amyloidosis (physiological), Alzheimer's disease, cardiomyopathy. Organs: CNS; heart

  • Amyloidosis-TTR (ATTR; unmutated transthyretin).
    • Transthyretin amyloidosis

Several different diseases can trigger the amyloid-forming defect by overproduction or by lack of or reduced degradation of certain proteins. Usually, the proteins formed are in solute form (e.g., serum amyloid A -SAA- an acute phase protein formed in the liver). They are proteolytically degradable. If their concentration increases, the proteins also reach the surrounding tissue. Here they are subjected to various enzymatic processes that lead to disturbances in protein folding.

Insoluble fibrillar complexes (amyloid fibrils) are formed by the aggregation of the resulting amino acid chains in a beta-folded sheet conformation. The fibrils cannot be phagocytized because they cannot be attacked by the macrophage system due to their conformational peculiarities. Thus, amyloid accumulates in various organs (kidney, liver, spleen, adrenal glands, gastrointestinal tract), so also in the skin with characteristic clinical and histological changes.

This process is similar to the pathogenic protein deposits in beta-sheet structure that characterize prion diseases. To date, > 20 amyloidogenic proteins are known.

Acquired amyloidoses:

Rare hereditary forms: see below Amyloidosis,hereditary

The average age of manifestation is 50-60 years. M:F=6:4

Eyelids (caused by pressing when coughing), axillae and navel, lower leg, chest area, also retroauricular. Also in artificially traumatized areas (pinch purpura) tongue (macroglossia).

Preliminary remark: The present description refers mainly to the amyloidosis types: AA, AL, AH.

• Integument: Flat reddish hardly elevated plaques with petechiae on skin and mucosa. Clinically, (spontaneous) extensive hemorrhages, especially on the flexor sides of the extremities, on the eyelids (so-called raccoon sign ) or also perianally can become manifest as initial dermatological symptoms of systemic amyloidosis. Furthermore, the occurrence of purpura at sites of tight-fitting clothing (so-called pinch purpura). Since the hemorrhages recur and are localized, hemosiderotic pigmentation occurs at these sites.
• Waxy, hard, nonpruritic papules and plaques; also deep subcutaneous painless nodules.
• If applicable, diffuse scleroderma- or myxedema-like indurations, especially on the face, hands, and feet.
• Rhagades especially around the lips and anogenital region, possibly patchy or diffuse alopecia.
• Infiltration of the fingers and palms with hyperkeratosis, possibly skin lesions reminiscent of porphyria cutanea tarda.
• Extracutaneous manifestations:
  • Fatigue, weight loss, paresthesias, edema, dyspnea, headache, syncope. Carpal tunnel syndrome, macroglossia (12-40%), painful dysphagia, hypertrophic cardiomyopathy with consecutive heart failure, pectanginal complaints, low voltage in ECG; hepatomegaly, nephropathy (nephrotic syndrome with possible renal failure).

The following procedure is recommended for diagnosis:

General Diagnostics:

• Anamnesis
• Physical examination with blood pressure and pulse
• Attention to the specific skin symptoms

Laboratory parameters:

• blood count including differential blood count, jolly corpuscles
• BSG (often significantly increased)
• Electrolytes (sodium, potassium, calcium)
• Renal retention parameters (creatinine, creatinine clearance, urea)
• Liver values (GOT, GPT; AP, gamma GT, LDH)
• Total protein and albumin in serum
• Electrophoresis with determination of the M-gradient; immunofixation electrophoresis in serum and urine
• Immunoglobulins (IgG, IgA, IgM) quantitative Free kappa and lambda light chains in serum quantitative incl. calculation of the quotient and difference
• 24 h collecting urine for the quantification of protein and albumin excretion and for the quantification of light chain excretion
• Quick (INR), PTT, factor X
  

Clinical differential diagnosis:

• Spectacle hematoma: In case of development of a "raccoon-sign": Posttraumatic spectacle hematoma, or intermittent bleeding after long term use of external or internal (ask for asthma sprays!) glucocorticoids.
• Waldenstrom's disease of the skin: Chronic, solitary or even disseminated, red or brown, mostly symptomless papules, plaques or nodules with smooth surface (mostly on the face or trunk). Lymph nodes or the spleen are enlarged in about 20-40% of patients. Cutaneous lesions due to homogeneous IgM deposits: formation of vesicles and blisters and, more rarely, small, symptomless skin-coloured papules on the buttocks and trunk (macroglobulinosis cutis). Non-specific lesions: the paraprotein may cause a hyperviscosity syndrome with purpura, cyanotic discoloration of the acra (fingers, toes, earlobes), dizziness, mucosal bleeding and visual disturbances. In the case of prolonged course of the disease secondary amyloidosis, occasionally disorders of kidney function. Furthermore vasculitic ulcers and livedovasculopathy.
• Colloidal milium (very rare): Juvenile form (cheeks, nose, perioral); adult form (face, ears, neck, back of the hand); papules the size of a glass pinhead, transparent in appearance, exceptionally yellowish-brownish or skin-coloured, soft, grouped papules; after a stab incision a gelatinous mass empties under pressure. In the adult form: occurrence in combination with other actinic changes.
• Hyalinosis cutis et mucosae: Head (eyelids), neck, extremities are affected. The first impression is a rigid facial expression with pronounced perioral and frontal furrow formation. Yellow-white, pinhead-sized nodules, confluence with plate-like, coarse plaques, some with a brownish, verrucous or crusty surface.
• Erythropoietic protoporphyria: Face and back of the hands are affected; appearing in early youth. Acute burning and itching after exposure to the sun. Formation of a severe dermatitis solaris with extensive, sharply defined erythema and oedema of the skin. Possible formation of blisters and crusts which heal with small, varioliform scars.
• Scleromyxoedema: Diffusely thickened facial skin with mimic rigidity, thickened skin of the distal extremities. Thickened, doughy skin of increased consistency, hyperpigmented, "too wide" skin which can be lifted off in large wrinkles. Multiple, dense, pinhead-sized, often itchy, lichenoid papules arranged in the skin lines, especially on the forehead, lateral facial region, retroauricular and in the neck. Internal organs: Sclerotherapy of renal and coronary arteries with corresponding symptoms, cerebral symptoms, pulmonary involvement.

Histological differential diagnosis:

• Macroglobulinosis cutis (Waldenstrom's disease of the skin): clumpy, extravascular, eosinophilic and PAS-positive homogeneous deposits in the whole dermis (partly also perifollicular), which are interspersed and bordered by a thinning lymphocytic infiltrate. Detection of the immunoglobulin light chain kappa.
• Protoporphyria erythropoetica: In the stratum papillare and reticular evidence of deposits of homogeneous eosinophilic, PAS-reactive amorphous masses around the capillaries and venules of the superficial vascular plexus. Sweat glands free from deposits. Often (accompanying) a (rather discrete) superficial and deep dermatitis with lymphocytes, neutrophilic granulocytes and occasionally eosinophils is found.
• Hyalinosis cutis et mucosae: Rather flat surface epithelium with distinct orthokeratotic hyperkeratosis. The papillary dermis is hyalinized, swollen and lacking in cells. Extracellular PAS-positive, diastase-resistant hyaline deposits in the papillary and reticular stratum around vessels and adnexa. In older foci these deposits are thickened like onion skin and can fill the entire papillary dermis. Strong hyaline deposits are also found around the eccrine sweat glands.
• Colloidalmilium: Homogeneous, circumscribed, amophilic or basophilic, PAS-positive colloidal conglomerates in the upper dermis. The deposits are cell-poor. Typical are the preparation-related fissures and gaps within the colloid nodule. The overlying epithelium is flattened and atrophic. Obligat is a solar elastosis (!).
• Mucinoses: Detection of acidic mucopolysaccharides with the alcian blue stain, which are diffusely or focally enriched in the dermis.

Primary form: Combination of chemotherapeutic agents, especially melphalan with glucocorticoids such as prednisolone (e.g. Decortin H) in medium dosage is recommended. Monotherapy with cyclophosphamide (e.g. Endoxan) 50-100 mg/day has also been used successfully in some cases. Treatment by internists.

Secondary form: S. AA-type amyloidosis, AL-type amyloidosis.

Amyloid is characterized by:

• Blue staining after contact with and dilute sulfuric acid.
• Eosinophilia in conventional HE staining
• Green-yellowish to red staining and birefringence in polarized light after staining with Congo red
• Electron microscopy by a meshwork of unbranched fibrils and by a non-fibrillar component (serum amyloid P component) common to all types of systemic and localized amyloid
• Beta-fold sheet structure, detectable by X-ray diffraction
• Differently associated protein types (detectable by laser microdissection of amyloid deposits followed by mass spectrometry)

1. Breathnach SM (1988) Amyloid and amyloidosis. J Am Acad Dermatol 18: 1-16.
2. Brownstein MH et al (1970) Systemic amyloidosis complicating dermatoses. Arch Derm 102: 1-7
3. Brownstein MH et al (1970) The cutaneous amyloidoses. Systemic forms. Arch Derm 102: 21-28
4. Dispenzieri A (2003) Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet 361: 1787-1789
5. Elston DM (2003) Primary systemic amyloidosis. Cutis 71: 276, 279-280
6. Hawkins PN (2003) Hereditary systemic amyloidosis with renal involvement. J Nephrol 16: 443-448.
7. Herbella FA et al (2001) 'Raccoon eyes' (periorbital haematoma) as a sign of skull base fracture. Injury 32: 745-747
8. Huang X et al (2015) The clinical features and outcomes of systemic AL amyloidosis: a cohort of 231 Chinese patients. Clin Kidney J 8:120-126
9. Kumar EK et al (2016) Kinetics of protein fibril formation: methods and mechanisms. Int J Biol Macromol doi:10.1016/j.ijbiomac.2016.06.052.
10. Lachmann HJ et al (2003) Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol 122: 78-84
11. Lubarsch O (1929) On the knowledge of unusual amyloid deposits. Virchows Arch 271: 867-889
12. Schirra A et al (2015) Perianal hemorrhagic erythema. JDDG 13: 707-709