follow @PCDSUKCreated: 29th March 2016 | Last Updated: 13th April 2016
Introduction
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Amyloidosis is the term used for a group of conditions where one or more body organs accumulate various insoluble proteins (amyloid) in amounts to cause dysfunction of the organ system. The amyloid deposits occasionally only affect one organ (in the skin this is referred to as primary localised cutaneous amyloidosis), but more often several organs are affected such as the heart, kidneys, gastrointestinal tract, nervous system and skin. Cutaneous amyloidosis and cutaneous manifestations of systemic amyloidosis are rare in Europe but far more frequent in South-East Asia, China and South America. This chapter, which focuses on the cutaneous features of amyloidosis, is set out as follows: |
Aetiology
Amyloidosis can be broadly classified as follows:
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Primary localised cutaneous amyloidosis (PLCA)
- In PLCA there is deposition of amyloid in the skin, with no systemic involvement
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PLCA is divided into three main groups - papular (lichen) amyloidosis, macular amyloidosis and nodular amyloidosis. Macular and papular amyloidosis may coexist
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Primary, and myeloma-associated, systemic amyloidosis
- This group of amyloidosis originates in the bone marrow and is sometimes referred to as amyloid L chain type (AL) amyloidosis
- The majority of cases are of unknown cause (primary systemic amyloidosis), although it can be secondary to myeloma
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The condition can affect the heart, kidneys, liver, gastrointestinal tract and central nervous system. Skin involvement occurs in about 30-40% of patients
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Secondary systemic amyloidosis
- This may occur as a complication of many chronic inflammatory diseases such as rheumatoid arthritis and other connective tissue disorders, tumours and haemodialysis
- It is also known as amyloid A (AA) amyloidosis and is the most common form of systemic amyloidosis worldwide
- The kidney, liver and spleen are the organs most affected
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Skin involvement is rarely a feature of the condition. Cutaneous features include petechiae, purpura and alopecia. Haemodialysis‐associated systemic amyloidosis can present with soft plaques in the skin
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Familial (hereditary) amyloidosis
- These are rare forms of amyloidosis
- The cutaneous features depend on the type
Clinical findings
Primary localised cutaneous amyloidosis (PLCA)
In PLCA there is deposition of amyloid in skin, with no systemic involvement. PLCA is divided into three main groups - papular (lichen) amyloidosis, macular amyloidosis and nodular amyloidosis. Macular and papular amyloidosis may coexist, and is referred to as mixed (biphasic, allotropic) PLCA.
Papular amyloidosis (syn. lichen amyloidosis)
- The most common form
- Appears to be more common in people of Chinese descent and in males, occuring most often between 50-60 years of age
- Lesions are often very itchy
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Distribution
- The shins are the most common site, other affected sites include the feet, thighs, extensor arms, and occasionally the trunk
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Morphology
- Multiple, hyperpigmented, scaly papules
- Papules may coalesce into plaques
Macular amyloidosis
- Appears to be more common in Asians, South Americans and Middle Easterners and usually presents in early adult life affecting women more frequently than men
- Mild-moderate itch is usual, however, some patients can be asymptomatic
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Distribution
- Lesions are usually distributed symmetrically over the upper back although can be localised to the interscapular area. The chest and arms can also be affected
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Morphology
- Multiple small grey-brown macules that may coalesce to form patches of darkened skin
- Although a reticulated or rippled pattern of pigmentation has been emphasised as a characteristic feature of macular amyloidosis, less than 50% of patients have this finding
Nodular amyloidosis
- Is the rarest form of PLCA
- It is usually asymptomatic, and mainly affects women
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Distribution
- Single or multiple lesions typically on the nose or legs, especially the feet, although any cutaneous site can be affected
- Disseminated cases have been reported
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Morphology
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Firm nodules and plaques vary in size and may be skin-coloured, pink-red or brown, and can have a waxy appearance
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Firm nodules and plaques vary in size and may be skin-coloured, pink-red or brown, and can have a waxy appearance
Systemic amyloidosis with cutaneous features
The systemic amylodosis most frequently associated with cutaneous features is primary, and myeloma-associated, systemic amyloidosis.
Primary, and myeloma-associated, systemic amyloidosis
- The mean age of onset is 65 years, with a slight male predominance
- The signs and symptoms are generally non-specific and include itch, fatigue, weight-loss, shortness of breath, a hoarse voice, numbness and tingling
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Cutaneous features
- Petechiae, purpura and ecchymoses are the most common skin findings. The face, especially around the eyelids and the periorbital skin (pinch purpura or raccoon eyes sign), and flexural regions are the most commonly affected sites. Haemorrhagic blisters may form following skin trauma such as pinching
- The most characteristic skin lesions consist of waxy papules, nodules, or plaques. Flexural sites such as the eyelids, retroauricular region, neck, axilla, inguinal and anogenital region are the predominant sites. Plaques may coalesce to form large tumefactive lesions
- Diffuse infiltrates may resemble infiltrates of scleroderma or myxoedema
- The nails may be crumbly and brittle
- Alopecia may occur and can be localised or generalised
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Other clinical features include the following:
- Carpal tunnel syndrome
- Macroglossia: amyloidosis is the most common cause
- Cardiac involvement can cause ischaemia, infarction, arrhythmias and cardiac failure
- The nephrotic syndrome
- Hepatomegaly
- Gastrointestinal involvement with malabsorption
- Peripheral neuropathy
Images
Please click on images to enlarge, or choose to download. Images must only be used for teaching purposes and are not for commercial use. Notice and credit must be given to the PCDS and any other named contributor.
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Figure: 1 Papular amyloidosis |
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Figure: 2 Papular amyloidosis |
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Figure: 3 Close-up of the above |
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Figure: 4 Macular amyloidosis A rippled pattern of pigmentation |
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Figure: 5 Close-up of the above |
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Figure: 6 Macular amyloidosis |
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Figure: 7 Close-up of the above |
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Figure: 8 Same patient |
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Figure: 9 Nodular amyloidosis |
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Figure: 10 Systemic amyloidosis Copied with kind permission from Dermatoweb |
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Figure: 11 Systemic amyloidosis Copied with kind permission from Dermatoweb |
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Figure: 12 Systemic amyloidosis - waxy-looking papules |
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Figure: 13 Amyloidosis - waxy appearance |
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Figure: 14 Systemic amyloidosis and glossitis Copied with kind permission from Dermatoweb |
Investigations
Skin biopsy - needed in all suspected cases
- May be negative in up to 50% of cases
- A skin biopsy should be sent for histology (standard stainings include H&E, toluidin blue and alkaline fuchsin. Amyloid stainings includes Congo red and thioflavin T), immunohistochemistry and electron microscopy
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The pathological features of a papule reveal an amorphous or fissured eosinophilic mass in the papillary dermis with associated thinning or obliteration of the rete ridges. Nodules and plaques may demonstrate diffuse amyloid deposition in the reticular dermis or subcutis. Amyloid depositions are usually not associated with an inflammatory infiltrate. The appearance of amyloid infiltration of the blood vessel walls, pilosebaceous units, arrector pili muscles, and lamina propria of sweat glands and infiltration around individual fat cells in the subcutis (known as amyloid rings) are characteristic findings
Primary, and myeloma-associated, systemic amyloidosis
- Anaemia occurs in less than 50% of cases
- ESR is higher than 50 mm/h in one half of cases
- Hepatic function is often abnormal, and the serum creatinine level is increased in 50% of patients. Proteinuria is present in the majority
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Immunoelectrophoresis of blood and concentrated urine samples is essential as standard electrophoresis may fail to demonstrate small quantities of monoclonal paraprotein or Bence-Jones protein associated with myeloma and other plasma cell dyscrasias. A skeletal scan may be useful, as 50% of patients with myeloma-associated amyloidosis have radiological abnormalities, compared with only 6% of those with primary systemic amyloidosis
Nodular cutaneous amylodosis
- Follow-up is required as it is important to assess for progression to systemic amyloidosis
- The assessment should include a full history and physical examination along with bloods (FBC, U&E, LFT, bone biochemistry, serum protein electrophoresis and urine protein electrophoresis) and an ECG
Management
- In general the treatment of PLCA is disappointing, although oral retinoids, such as acitretin, are showing some promise in the treatment of papular (lichen) amyloidosis. Milder cases may get some improvement with potent topical steroids, and pruritus may be improved with topical cooling agents such as 1-2% menthol in aqueous cream, sedating antihistamines or phototherapy. Nodular lesions can be treated by surgery or laser, however, recurrence is common
- In systemic amyloidosis, when there is an identifiable underlying condition, all efforts should be made to slow down or stop the progress of the disease. For instance, amyloidosis associated with myeloma should primarily be managed by treating the underlying myeloma in cooperation with experienced oncologists. Often, immunosuppressive therapies are a core component in the treatment of systemic amyloidosis secondary to inflammation