Amyloidosis systemic (overview) E85.9

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Accompanying amyloidosis; Altersamyloidosis; Amyloidosis; Amyloidosis idiopathic systemic; Amyloidosis pericollagene; Amyloidosis perireticular; Amyloidosis secondary systemic; amyloidosis senile; Amyloidosis systemic; Generalized amyloidoses; paraamyloidosis; Paramyloidosis; scleroderma amyloidosum; senile amyloidosis; Systemic amyloidoses; Systemic amyloidosis

Definition
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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
  • secondary (reactive)

systemic amyloidosis.

Another classification differentiates between:

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

The systemic amyloidoses must be separated from the localised (non-systemic) amyloidoses.

Classification
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Systemic amyloidoses (rare, in contrast to the non-systemic cutaneous amyloidoses only minor dermatological relevance):

  • Hereditary amyloidoses (rare; 5% of all cases)
    • AATR (Mutated Transthyretin)
      • FAP (familial amyloid polyneuropathy)
      • FAC (familial cardiomyopathy)
    • Other very rare hereditary amyloidoses
  • Acquired systemic (generalized) amyloidoses (95% of all cases)
    • Amyloidosis of the AL or AH type (immunoglobulin type - L stands for light chain, H stands for heavy chain)
      • gammopathy-associated amyloidosis
      • Myeloma-associated amyloidosis.
    • Amyloidosis of the AA type (serum amyloid A):
      • Amyloidosis in chronic inflammation; increased formation of the acute phase protein serum amyloid A in inflammation (rheumatoid arthritis, chronic inflammatory bowel disease, syphilis, leprosy, tuberculosis, cystic fibrosis, etc.)
    • Amyloidose-ß2 microglobulin associated
      • Amyloidosis in long-term dialysis (beta-2-microglobulin deposits); long-term dialysis leads to accumulation of A-ß2 because it is not dialyzed with it 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 which are deposited in organs during the aging process. Occurrence: Amyloidosis of old age (physiological), Alzheimer's disease, cardiomyopathy. Organs: CNS; heart

    • Amyloidosis TTR (ATTR; unmutated transthyretin)

Occurrence/Epidemiology
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Rare disease. Prevalence: 8/1 million inhabitants.

Etiopathogenesis
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Several different diseases can trigger the amyloid-forming maldevelopment through overproduction or through missing or reduced breakdown of certain proteins. Usually, the formed proteins are present in dissolved 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 enter the surrounding tissue. Here they are exposed to various enzymatic processes. By aggregation of the resulting amino acid chains in a beta-sheet conformation, insoluble fibrillar complexes (amyloid fibrils) are formed. The fibrils cannot be phagocytized as they are not attackable due to their conformational peculiarities. Thus, amyloid accumulates in various organs (kidney, liver, spleen, adrenal glands, gastrointestinal tract), including the skin, where it leads to characteristic clinical and histological changes.

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

Acquired amyloidoses:

Amyloidosis type (short name) precursor protein Associated clinical picture
AA serum amyloid A Chronic inflammatory diseases such as: rheumatoid arthritis, tuberculosis, leprosy, chronic inflammatory bowel diseases, etc.
Al and AH

immunoglobulins:

Light (L) Chain

Heavy (H)chain

Monoclonal gammopathies (see MGUS), multiple myeloma, M. Waldenström
Aß2 Microglobulin ß2 Microglobulin Chronic dialysis (see there)
ATTR Transthyretin Senile systemic amyloidosis(transthyretin amyloidosis)

Rare hereditary forms: S.u. amyloidosis, hereditary

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

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

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

  • Integument: Flat reddish plaques with hardly elevated petechiae on the skin and mucous membrane. Clinically, (spontaneous) flat bleedings especially on the flexion sides of the extremities, on the eyelids (so-called raccoon-sign = raccoon-sign) or perianal can become manifest as dermatological first symptoms of system amyloidosis. Further occurrence of a purpura in places of tight-fitting clothes (so-called pinch purpura). Since the bleeding recurs and is localised, haemosiderotic pigmentation occurs in these areas.
  • Further signs of system amyloidosis are:
    • Waxy, hard, non-itching papules and plaques; also deep subcutaneous, painless nodules.
    • Possibly diffuse scleroderma or myxedema-like indurations, especially in the area of the face, hands and feet.
    • Rhagades especially in the area of the lips and the anogenital region, possibly spotty or diffuse alopecia.
    • Infiltration of the fingers and palms with hyperkeratosis, possibly skin changes reminiscent of porphyria cutanea tarda.
      • Extracutaneous manifestations: fatigue, weight loss, paraesthesia, edema, dyspnea, headache, syncope. Carpal tunnel syndrome, macroglossia (12-40%), painful dysphagia, cardiomyopathy(hypertrophic cardiomyopathy) with consecutive heart failure, hepatomegaly, nephropathy (nephrotic syndrome, renal insufficiency).

Histology
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Amyloid deposits in the affected skin, deep in the dermis. Coatings of small blood vessels and adnexes, especially sweat glands. Annular coating of subcutaneous lipocytes (so-called amyloid rings). Deposits in the affected internal organs. The reaction with antibodies against immunoglobulins is positive. Antibodies against keratins (e.g. cytokeratin) react negatively.

Diagnosis
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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

Differential diagnosis
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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.

Internal therapy
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Progression/forecast
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Serious prognosis, depending on cardiovascular involvement. Mean survival time: 6-18 months.

Literature
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  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 amyloidosis. 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. Schirra A et al (2015) Perianal hemorrhagic erythema. JDDG 13: 707-709

Disclaimer

Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Authors

Last updated on: 29.10.2020