Amyloidosis of the skin

Cutaneous amyloidosis is a metabolic disorder in which amyloid is deposited in the skin.

Research has established that amyloid is a glycoprotein of protein nature. The deposition of this protein leads to disruption of tissue and organ function.

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Causes and pathogenesis of cutaneous amyloidosis

The causes and pathogenesis of amyloidosis are not fully understood. According to some authors, the disease is based on a mutation that leads to the formation of a clone of cells of mesenchymal origin - amyloidoblasts, synthesizing the fibrillar protein amyloid.

Amyloidosis is a mesenchymal dysproteinosis accompanied by the appearance of abnormal fibrillar protein in tissues with the formation of a complex substance, amyloid, in the interstitial tissue.

V.V. Serov and G.N. Tikhonova (1976), L.N. Kapinus (1978) showed that the amyloid substance is a glucoprotein, the main component of which is the fibrillar protein (F-component). Electron microscopy showed that amyloid fibrils have a diameter of 7.5 nm and a length of 800 nm, and are devoid of transverse striation. The fibrillar protein is synthesized by mesenchymal cells - amyloidoblasts (fibroblasts, reticular cells). In tissue, it combines with proteins and polysaccharides of blood plasma, which are its second obligatory component (P-component); in an electron microscope, it appears as rod-shaped structures with a diameter of 10 nm and a length of 400 nm, consisting of pentagonal formations. Amyloid fibrils and the plasma component combine with tissue glycosaminoglycans, and fibrin and immune complexes join the resulting complex. The fibrillar and plasma components have antigenic properties. GG Glenner (1972) believes that amyloid can arise from monoclonal light chains and immunoglobulins, which are part of amyloid fibrils regardless of the clinical classification of amyloid in both primary and secondary amyloidosis. G. Husby et al. (1974) also describe the formation of amyloid masses from non-immunoglobulin protein (amyloid A). Both types of amyloid are usually found together.

The morphogenesis of amyloidosis, according to V.V. Serov and G.N. Tikhonova (1976), V.V. Serov and I.A. Shamov (1977), consists of the following links:

1. transformation of elements of the macrophage-histiocyte system with the appearance of a clone of cells capable of synthesizing the fibrillar component of amyloid;
2. synthesis of fibrillar protein by these cells;
3. aggregation of fibrils with the formation of a "framework" of amyloid substance and
4. connections of the fibrillar component with proteins and glucoproteins of plasma, as well as tissue glycosaminoglycans.

Amyloid formation occurs outside the cells in close connection with connective tissue fibers (reticulin and collagen), which gives grounds to distinguish two types of amyloid - perireticular and pericollagen. Perireticular amyloidosis occurs mainly in lesions of the spleen, liver and kidneys, adrenal glands, intestines, vascular intima, and pericollagen is characteristic of amyloidosis of the vascular adventitia, myocardium, striated and smooth muscle tissue, nerves and skin.

Amyloid masses are stained pale pink with hematoxylin and eosin, and yellow with the Van Gieson method. The specific dye Congo red stains it red. A special method for detecting amyloid is also reactions with thioflavin T followed by immunofluorescence microscopy.

Depending on the causative factor, according to the classification of V.V. Serov and I.A. Shamov (1977), amyloidosis is divided into the following forms: idiopathic (primary), hereditary, acquired (secondary), senile, local (tumor).

The skin is most often affected in primary localized, then in primary systemic amyloidosis. In familial forms of amyloidosis, skin changes are less frequent than in systemic. Skin changes in systemic amyloid are polymorphic. Hemorrhagic rashes are more common, but asymptomatic, yellowish nodular-nodular elements located mainly on the face, neck, chest, and in the oral cavity, often accompanied by macroglossia, are more typical. There may be spotty, scleroderma-like, plaque foci, changes similar to ceantomatous and myxedematous lesions, in rare cases - bullous reactions, alopecia. Secondary systemic amyloidosis usually occurs without skin changes. Secondary local amyloidosis of the skin develops against the background of various skin diseases, mainly in the foci of lichen planus and neurodermatitis.

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Pathomorphology of skin amyloidosis

In localized papular amyloidosis, amyloid masses are found in the lesions, usually in the papillary layer of the dermis. In fresh lesions, small aggregates are noted in reduced papillae of the skin or directly under the epidermis. These deposits are often localized pericapillary, and around them are numerous reticulin fibers, a moderate number of fibroblasts, and in some cases, chronic inflammatory infiltrates.

In large amyloid masses melanin-containing macrophages, fibroblasts, histiocytes, and sometimes lymphocytes are visible. Occasionally, minor amyloid deposits may be observed in the thickened epidermis. The skin appendages are mostly intact.

The histogenesis of amyloid lichen has not been fully elucidated. There is evidence of the epidermal origin of amyloid due to focal damage to epithelial cells with their transformation into fibrillar masses and then into amyloid. The participation of keratin in the formation of amyloid is evidenced by the reaction of amyloid fibrils with antibodies against human keratin, the presence of disulfide bonds in amyloid, and also the indirect positive effect of the use of retinoic acid derivatives.

Primary macular cutaneous amyloidosis

Primary spotted cutaneous amyloidosis is characterized by the appearance of significantly itchy spots 2-3 cm in diameter, brown or brown in color, which are localized on the trunk, but most often - in the upper part of the back, interscapular region. A case of the appearance of pigmented amyloidosis around the eyes is described. The spots tend to merge and form hyperpigmented areas. Reticulated hyperpigmentation is a characteristic feature of spotted amyloidosis. Simultaneously with hyperpigmentation, hypopigmented foci may occur, which resembles poikiloderma. Patients complain of itching of varying intensity. In 18% of cases, itching may be absent. Small nodules (nodular amyloidosis) appear simultaneously with spotted rashes.

During pathomorphological examination, amyloid is detected in the papillary layer of the dermis. The development of maculopapular amyloidosis in a patient with the Epstein-Barr virus is described. After treatment with acyclovir and interferon, the maculopapular rashes resolved significantly, which confirms the role of viruses in the deposition of amyloid in tissues. The maculopapular form of amyloidosis occurs in adults, men and women are equally affected. The disease is common in Asia and the Middle East, and rare in Europe and North America.

Nodular-plaque form of cutaneous amyloidosis

The nodular-plaque form is a rare variant of primary cutaneous amyloidosis. It mainly affects women. Single or multiple nodules and plaques are most often localized on the shins, sometimes on the trunk and limbs. On the anterior surface of both shins, numerous, pinhead- to pea-sized, spherical, shiny nodules are strictly symmetrically located, closely adjacent to each other, but not merging, and separated by narrow grooves of healthy skin. Some lesions have the character of wart-like formations with horny layers and scales on the surface. The rash is accompanied by excruciating itching, and areas of scratching and lichenification of the skin are visualized. In most patients, the level of alpha- and gamma-globulins in the blood serum is elevated. Combinations of nodular plaque amyloidosis with diabetes, Sjogren's syndrome and the transition of this form of amyloidosis to systemic amyloidosis with the involvement of internal organs in the pathological process are described.

Significant amyloid deposition is found in the dermis, subcutaneous fat layer, blood vessel walls, sweat gland basement membrane, and around fat cells. Amyloid masses may be found among chronic inflammatory infiltrate cells, which contain plasma cells and foreign body giant cells. Biochemical analysis revealed peptides with molecular weights of 29,000; 20,000, and 17,000 in amyloid fibrils. Immunoblotting revealed staining of the peptide with a molecular weight of 29,000 by antibodies to the immunoglobulin alpha chain. There is evidence of a combination of deposits of light χ- and λ-chains of immunoglobulins. These materials indicate the immunoglobulin nature of amyloid in this form of amyloidosis. It is assumed that the foci accumulate plasma cells secreting light L-chains of immunoglobulins, which are phagocytized by macrophages and converted into amyloid fibrils. As in the case of nodular amyloidosis, in bullous amyloidosis it is necessary to exclude systemic amyloidosis. A peculiar form of bullous amyloidosis was described by T. Ruzieka et al. (1985). Clinically, it is similar to atypical herpetiform dermatitis due to itchy erythematous urticarial and bullous rash, spotted hyper- and depigmentation. There are also foci of lichenification and ichthyosiform hyperkeratosis. Histological examination reveals amyloid deposition in the upper layers of the dermis. According to electron microscopy, the blisters are located in the zone of the luminal plate of the basement membrane. Immunohistochemical studies using antisera against various amyloid fibril proteins and monoclonal antibodies against IgA were negative.

Secondary systemic amyloidosis

Secondary systemic amyloidosis in the skin can develop mostly with various chronic suppurative processes in patients with myeloma and plasmacytoma. Clinical changes in the skin are rare, but histologically, when stained with alkaline Congo red, amyloid masses can be detected in it, which look green under a polarizing microscope. In these cases, they can be seen around sweat glands, sometimes around hair follicles and fat cells.

Secondary localized amyloidosis

Secondary localized amyloidosis may develop against the background of various chronic dermatoses, such as lichen planus, neurodermatitis, and some skin tumors: seborrheic wart, Bowen's disease and basalioma. In spotted amyloidosis, amyloid lichen, in the circumference of keratomas or epitheliomas, in chronic eczema, so-called amyloid bodies (amyloid lumps, amyloid clots) are often observed. They are most often localized in the papillary layer of the dermis, located in the form of large groups. Sometimes individual papillae are completely filled with homogeneous masses, but they can also be observed in deeper parts of the dermis, more often in the form of lumps. They are eosinophilic, PAS-positive, specifically stained with Congo red, yellowish-green in a polarizing microscope, fluoresce with thioflavin T and give an immune reaction with specific antisera. Amyloid bodies are often surrounded by numerous connective tissue cells, the processes of which are associated with them, in connection with which some authors believe that these masses are produced by fibroblasts.

Familial (hereditary) amyloidosis

Familial (hereditary) amyloidosis has been described in both familial and localized cutaneous amyloidosis. A family has been described in which affected members had hyperpigmentation and severe itching. The disease is believed to be inherited in an autosomal dominant manner. Primary! Cutaneous amyloidosis has been reported in identical twins who, in addition to amyloidosis, suffered from various congenital anomalies. The literature describes cases of cutaneous amyloidosis combined with congenital pachyonychia, congenital dyskeratosis, palmoplantar keratoderma, multiple endocrine dysplasias, etc.

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Histopathology

Pathomorphological examination reveals diffuse deposition of amyloid in the skin and subcutaneous fat tissue in the walls of blood vessels, membranes of sweat glands and fat cells.

Symptoms of cutaneous amyloidosis

Currently, amyloidosis is classified into the following forms:

1. Systemic amyloidosis
   • primary (myeloma-associated) systemic amyloidosis
   • secondary systemic amyloidosis
2. Cutaneous amyloidosis
   • primary cutaneous amyloidosis
   • primary nodular amyloidosis
   • spotted amyloidosis
   • nodular amyloidosis
   • nodular plaque amyloidosis
   • secondary (tumor-associated) cutaneous amyloidosis
3. Familial (hereditary) amyloidosis or a combination of amyloidosis with familial syndromes.

Primary systemic amyloidosis

Primary systemic amyloidosis occurs without a previous disease. In this case, organs of mesenchymal origin are affected: tongue, heart, gastrointestinal tract and skin. Myeloma-associated amyloidosis is also included in primary systemic amyloidosis. In primary systemic amyloidosis, skin rashes are observed in 40% of cases, which are polymorphic and manifest as petechiae, purpura, nodules, plaques, nodes, tumors, poikiloderma, blisters, scleroderma-like changes. Elements tend to merge. Purpura is most common (in 15-20% of patients). Purpura appears around the eyes, on the extremities, in the oral cavity after injuries, overexertion, physical exertion, vomiting, severe coughing, since there is an increase in pressure in the vessels surrounded by amyloid.

Glossitis and macroglossia occur in 20% of cases, are often early symptoms of primary systemic amyloidosis and can lead to dysphagia. The tongue increases in size and becomes furrowed, and impressions from the teeth are visible. Papules or nodes with hemorrhages are sometimes found on the tongue. Vesicular rashes have been described, which are very rare. Vesicles with hemorrhagic contents appear in areas of greatest trauma (arms, legs) and are clinically very similar to blisters in congenital bullous epidermolysis and porphyria cutanea tarda.

In primary systemic amyloidosis, diffuse and focal alopecia, scleroderma-like and scleromyxedema-like rashes have also been described.

Amyloid Elastosis

A peculiar form of systemic amyloidosis is amyloid elastosis, clinically manifested by nodular rashes, and histologically by amyloid deposition around the elastic fibers of the skin and subcutaneous tissue, serous rims, and walls of muscular blood vessels. It has been previously shown that the amyloid component P associated with microfibrils of normal elastic fibers can participate in the deposition of amyloid fibrils.

In macular amyloidosis of the skin, minor deposits of amyloid are found in the dermal papillae. They can be detected, although not always, only by special staining. The amyloid masses in this type of amyloidosis may be in the form of globules or homogeneous masses located immediately beneath the epidermis and partly in its basal cells. As a result, there may be incontinence of the pigment, which is often found in the melanophages of the papillary layer of the dermis, which is usually accompanied by an inflammatory reaction. Clinically, macular amyloidosis is manifested by hyperpigmented spots of varying sizes, located mainly on the skin of the back, or reticular foci. Along with the spots, nodular eruptions similar to those observed in amyloid lichen can be found. It has been shown that in cases of macular amyloidosis caused by contact with nylon, the main component of amyloid is altered keratin.

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Secondary systemic amyloidosis

Secondary systemic amyloidosis develops in people suffering from chronic diseases such as tuberculosis, lepromatous leprosy, Hodgkin's disease, rheumatoid arthritis, Behchst's disease, ulcerative colitis. In this case, parenchymatous organs are affected, but the skin is not affected.

Primary localized cutaneous amyloidosis

Primary localized amyloidosis in the skin most often manifests itself as papular amyloidosis, less often as nodular-plaque, spotty and bullous.

Papular amyloidosis most often develops on the skin of the shins, but can also occur in other places. Familial cases are observed. The lesions are represented by itchy dense hemispherical flat or conical papules, closely adjacent to each other. Merging, they form large plaques with a warty surface.

Differential diagnosis

Amyloidosis should be distinguished from lichen myxedema, lichen planus, and nodular pruritus.

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Treatment of cutaneous amyloidosis

In mild cases of primary localized cutaneous amyloidosis, strong topical glucocorticosteroids are effective. In Ecuador, where there are many cases of primary cutaneous amyloidosis, good results were observed with topical application of 10% dimethyl sulfoxide (DMSO). In the nodular form, otretinate is quite effective, but after stopping the drug, the disease often recurs. Cyclophosphamide (50 mg per day) significantly reduces itching and resolves papules in the nodular form of cutaneous amyloidosis.

Some authors recommend treating cutaneous amyloidosis with resorchin (delagyl), long-term, 0.5 g per day, laser therapy, 5% unithiol - intramuscularly.