Amyloidosis

What is amyloidosis?

Amyloidosis is the term used for a group of diseases where one or more body organs accumulate various insoluble proteins (amyloid) in amounts to cause dysfunction of the organ system. Organs often affected include the heart, kidney, gastrointestinal tract, nervous system and skin. Amyloidosis of the skin is called cutaneous amyloidosis. In this condition, amyloid or amyloid-like proteins are deposited in the dermis.

Types of amyloidosis

There are three important types of amyloidosis.

Primary amyloidosis

• Primary amyloidosis is a disorder of protein metabolism that originates in the bone marrow and is occasionally associated with multiple myeloma. It is sometimes also referred to as amyloid L chain type (AL) amyloidosis.
• Primary systemic amyloidosis affects the heart, kidneys, liver, gastrointestinal tract and central nervous system. Skin involvement occurs in about 30–40% of patients.
• Localised primary amyloidosis affects specific organs such as the skin (primary cutaneous amyloidosis), heart, eye, airway and bladder.

Types of primary localised cutaneous amyloidosis include:

• Lichen amyloidosis
• Macular amyloidosis
• Nodular amyloidosis
• Amyloidosis cutis dyschromica.

Secondary systemic amyloidosis

• Secondary systemic amyloidosis occurs as a complication of many chronic inflammatory diseases such as rheumatoid arthritis and osteomyelitis.
• 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 are most affected in secondary systemic amyloidosis. Skin involvement is rarely a feature of the disease.

Familial (hereditary) amyloidosis

Familial amyloidosis is a rare form of amyloidosis that is inherited and most commonly causes cardiomyopathy and neuropathy in middle age. The most common form, known as ATTR amyloidosis, is due to a mutation in the transthyretin (TTR) gene on chromosome 5 and leads to faulty hepatic transthyretin protein.

What are the clinical features of primary amyloidosis?

Distinctive clinical features are found for each type of primary amyloidosis.

Systemic amyloidosis

The signs and symptoms of primary systemic amyloidosis are generally non-specific and include:

• Fatigue
• Weight-loss
• Oedema
• Shortness of breath
• Lightheadedness
• Numbness, tingling sensation
• Hoarseness.

These may precede the diagnosis of amyloidosis by up to two years. However, when they present together with the following specific symptoms, systemic amyloidosis should be considered a possible diagnosis.

• Carpal tunnel syndrome: disturbance of median nerve function in the wrist as the nerve passes through the carpal tunnel.
• Skin lesions
  • The most common skin findings are purpura: petechiae (small red blood spots) and ecchymoses (small, flat blood spots that are a round or irregular shape and bluish/purplish).
  • Waxy papules, nodules or plaques may be found around the eyelids, neck, groin and anogenital area.
  • Blood-filled blisters may form, for example on pinching the skin.
  • The nails may be crumbly and brittle (nail dystrophy).
  • Patches of hair loss may arise (diffuse alopecia).
• Macroglossia: this refers to an enlarged and firm tongue covered in blood spots, plaques and blisters.
• Oedema (tissue swelling) develops as a result of heart failure or nephrotic syndrome (kidney disease).
• Hepatomegaly (enlarged liver).

Hereditary amyloid

Purpura due to amyloidosis

Purpura due to amyloidosis

Macroglossia due to systemic amyloidosis

Macroglossia due to systemic amyloidosis

Macroglossia due to systemic amyloidosis

Lichen amyloidosis

• Also called papular amyloidosis
• Lichen amyloidosis is one of the two common forms of primary localised cutaneous amyloidosis.
• It presents as an intensely itchy rash on the shins, thighs, feet, and forearms.
• Lesions consist of multiple raised spots (papules) that are scaly and red/brown.
• Papules may coalesce into thickened plaques.
• It appears to be more common in people of Chinese descent and males.
• It most often occurs in people 50–60 years of age.
• It may be a variant of lichen simplex.

Lichen amyloidosis

Lichen amyloidosis

Lichen amyloidosis

Macular amyloidosis

• In macular amyloidosis, lesions appear as flat dusky-brown or greyish coloured spots that may coalesce to form patches of darkened skin.
• The degree of itchiness varies from mild to severe.
• Lesions are usually distributed over the upper back between the shoulder blades, on the chest and sometimes on the arms.
• It appears to be more common in Asians, South Americans and Middle Easterners.
• It usually presents in early adult life and affects women more frequently than men.
• Macular amyloidosis is said to be equally as common as lichen amyloidosis, but is probably more common due to its vague presentation and misdiagnosis.

Macular amyloidosis

Macular amyloidosis

Macular amyloidosis

Nodular primary localised cutaneous amyloidosis

• Also known as amyloidosis cutis nodularis atrophicans and tumefactive amyloidosis
• Nodular primary localised cutaneous amyloidosis is the rarest form of primary localised cutaneous amyloidosis.
• Single or multiple firm nodules or plaques may occur on the trunk, limbs, extremities, face, and genitals.
• Nodular primary localised cutaneous amyloidosis is usually symptomless, and patients seek medical attention for their appearance.
• Nodules may be a few millimetres to a few centimetres in size and may be pinkish brown to red.
• Lesions tend not to ulcerate, but some may crack or split, particularly those on the soles of the feet.

Nodular amyloidosis

Amyloidosis cutis dyschromicum

Amyloidosis cutis dyschromica is a newly described form of primary cutaneous amyloidosis that causes localised hyperpigmentation and hypopigmentation.

How is the diagnosis of amyloidosis made?

The diagnosis of the various types of primary cutaneous amyloidosis is made by its clinical appearance and by the characteristic histology changes seen on skin biopsy. See also systemic amyloidosis pathology.

What is the treatment of systemic amyloidosis?

Nonspecific treatment

Treatment is directed at maintaining the function of affected organs. For example, kidney failure can be treated with dialysis and congestive heart failure with diuretics.

Specific treatment

• Chemotherapy with melphalan and prednisone or dexamethasone (oral corticosteroids) can control systemic amyloidosis.
• In secondary amyloidosis, colchicine can inhibit amyloid deposition while treatment is directed against the primary cause.
• Targeted monoclonal antibodies in use for systemic amyloidosis include lenalidomide and bortezomib.
• Bone marrow ablation may be undertaken to remove the plasma cells and is followed by autologous stem cell transplantation.
• Hereditary ATTR amyloidosis is treated by diflunisal, or tafamidis (which stabilises the abnormal transthyretin protein). Liver transplantation is reserved for the most severely affected individuals.

Prognosis

Most untreated patients die within 1–2 years of diagnosis of primary systemic amyloidosis from heart or kidney failure.

What is the treatment of primary cutaneous amyloidosis?

The treatment of lichen and macular amyloidosis is focused on relieving itch. Sedating antihistamines can be moderately effective. Topical and intralesional steroids may provide some relief if used with other treatments. Other treatments include topical dimethyl sulfoxide (DMSO) and phototherapy (UVB or PUVA).

Surgical treatment to remove amyloid deposits includes laser vaporisation, dermabrasion, and excision of individual lesions.

The main aim of treatment of nodular primary localised cutaneous amyloidosis is to improve the appearance. Several methods are used and include antibiotics, topical and intralesional corticosteroids, cryotherapy, dermabrasion, shaving, curettage and electrodesiccation, carbon dioxide laser, and pulsed dye laser.

Primary cutaneous amyloidosis tends to persist or recur after treatment, but remains confined to the skin and does not evolve to systemic disease.