Macular Amyloidosis

Background

Primary localized cutaneous amyloidosis (PLCA) is characterized by extracellular deposition of heterogeneic amyloid proteins in the skin without systemic involvement. Types of PLCA include the following^[1] :

• Macular amyloidosis
• Lichen amyloidosis
• Nodular amyloidosis
• Biphasic amyloidosis (lichen amyloidosis and macular amyloidosis)

Macular amyloidosis is a relatively uncommon condition thought to result from a combination of genetic and environmental causes with prolonged friction a key pathogenic factor. However, the precise molecular mechanisms underlying its pathogenesis are not known.^[2] Macular amyloidosis has been reported in association with multiple endocrine neoplasia type 2A. The cardinal triad of this autosomal dominant syndrome is medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism.^[3]  Macular amyloidosis has also been associated with systemic diseases (autoimmune diseases in particular).^[4]

Macular amyloidoisis is a chronic disease. Cosmetic disfigurement and severe pruritus significantly impair quality of life.^[5] In a study of 101 Chinese patients with PLCA, Fang et al reported significantly decreasing average scores in social functioning and mental health due to pruritus. Because of its significant impact on quality of life, pruritus management is an important component of treatment. Additionally, the study found that lesions on visible parts of the body, such as the face and hands, decrease quality of life more than lesions that can be hidden.^[6]

Macular amyloidoisis is usually diagnosed clinically. The most common dermoscopic finding of macular amyloidosis is a central hub of either white or brown surrounded by various configurations of brownish pigmentation, including fine radiating streaks, dots, leaf-like projections, and bulbous projections.^[7] For cases with atypical presentations, skin biopsy may be necessary.

Therapeutic modalities that have been suggested include topical and systemic medications, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers.^{[8, 9, 10]} However, evidence from randomized, controlled trials is lacking, and effectiveness is based on small studies and case reports. No standardized treatment has been established.^[11]

The incidence of macular amyloidosis is more common among Asians, Middle Easterners, and South Americans than in other people. In many studies, macular amyloidosis seems to affect women more frequently than men.^[5] Macular amyloidosis is a disease of the adult population.

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Pathophysiology

Amyloidosis is a generic term that signifies the abnormal extracellular tissue deposition of one of a family of biochemically unrelated proteins that share certain characteristic staining properties, including apple-green birefringence of Congo red–stained preparations viewed under polarizing light. Under electron microscopy (EM), amyloid deposits are composed of linear, nonbranching, aggregated fibrils that are 7.5-10 nm thick and of indefinite length and arranged in a loose meshwork.^[12]

X-ray diffraction crystallography and infrared spectroscopy reveal that these fibrils have a meridional, antiparallel, beta-pleated sheet configuration, with polypeptide chains arranged perpendicular to the long axis of the fibrils.

Amyloid deposits contain (in addition to the fibrillar component) a nonfibrillar protein referred to as amyloid-P (Am-P). This protein is identical to normal plasma globulin, known as serum amyloid-P (SAP). Am-P constitutes 14% of the dry weight of amyloid. This protein is also found in the microfibrillar sheath of elastic fibers. SAP is closely related to the acute-phase reactant C-reactive protein (CRP) and has been shown to be an elastase inhibitor.^[13]

The SAP and the beta-pleated sheet configurations are thought to protect amyloid deposits from degradation and phagocytosis, leading to persistence of the deposits.

Both macular and lichen amyloidosis can occur in the same patient, sometimes called biphasic amyloidosis.^{[1, 14]}  An unusual case has been reported of a male patient with widespread macular amyloidosis and concurrent hepatits B and C infections.^[4] Amyloid deposits in macular amyloidosis and lichen amyloidosis bind to antikeratin antibodies. These deposits contain sulfhydryl groups pointing to altered keratin as a source for these deposits. Apaydin et al found no differences in staining characteristics of cytokeratins between macular amyloidosis and lichen amyloidosis.^[15] Interestingly, in their study, all the cytokeratins detected in amyloid deposits were of basic type (type II). This may be because, in amyloidogenesis, acidic cytokeratins such as cytokeratin 14 are degraded faster than basic types.

A pathogenic missense mutation was identified in the OSMR gene that encodes the oncostatin M (OSM) receptor β (OSMR-β) and has been identified in both Brazilian and Chinese families with manifestations of familial primary localized cutaneous amyloidosis.^{[16, 17, 18]} Lin at al found a point mutation in the IL-31 receptor A gene in a family with hereditary autosomal dominant primary localized cutaneous amyloidosis.^[19]

The exact origin of amyloid deposits in macular amyloidosis has not been determined. Two theories have been proposed to explain the origin of the amyloid deposits: fibrillar body theory and secretory theory. These theories are not mutually exclusive, and both could be possible.

Fibrillar body theory

Fibrillar body theory was proposed by Hashimoto and suggests that the necrotic epidermal cells (colloid bodies) are transformed into amyloid by dermal macrophages and fibroblasts by a process called filamentous degeneration. The absence of amyloid deposits in other dermatoses with colloid bodies (eg, lichen planus) is explained by the brisk inflammatory reaction clearing them promptly in lichen planus, while the lack of inflammatory cells leads to the formation of amyloid deposits in macular amyloidosis.^{[20, 21]} This theory does not explain how the alpha type of keratin tertiary structure is degraded and converted into the beta-pleated sheet configuration of amyloid.

Secretory theory

Secretory theory, proposed by Yamagihara et al, suggests that the amyloid in macular amyloidosis is secreted by disrupted basal cells and is assembled at the dermoepidermal junction.^[22]

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Physical Examination

Macular amyloidosis is a pruritic eruption that is variable in severity and consists of small, dusky-brown or grayish hyperpigmented macules and patches that have a reticulated or rippled pattern distributed symmetrically over the upper back and, in some patients, the extremities.^{[23, 24]} Frequently, patients seek medical attention because of the hyperpigmentation. (See the images of macular amyloidosis below.)

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Reddish brown patch on the back characteristic of macular amyloidosis. Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.

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Reticulated pattern of pigmentation on the shoulder of a patient with macular amyloidosis. Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.

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Close-up of the above patient's eruption. Courtesy of Hon Pak, MD, and reviewed by Ross Levy, MD.

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Approach Considerations

Macular amyloidoisis is usually diagnosed clinically. The most common dermoscopic finding of macular amyloidosis is a central hub of either white or brown surrounded by various configurations of brownish pigmentation, including fine radiating streaks, dots, leaf-like projections, and bulbous projections.^[7] For cases with atypical presentations, skin biopsy may be necessary to confirm the diagnosis.^[24]

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Histologic Findings

Many stains can demonstrate amyloid deposits in the skin. The best known is the Congo red stain, which under polarizing light gives apple-green birefringence. Other stains include periodic acid-Schiff (PAS); methyl violet; crystal violet; various cotton dyes (eg, pagoda red, Sirius red); and the fluorescent dyes thioflavin-T and Phorwhite BBU. Immunohistochemical staining of CK5 and high molecular weight heparin keratin on specimens may be a more useful diagnostic test than hematoxylin and eosin staining or crystal violet staining.^[26]

In macular amyloidosis, the amyloid deposits are usually found within the dermal papillae.^[24] The amyloid deposits are usually globular, resembling colloid bodies, and they may be in contact with basal cells at the dermoepidermal junction. The deposits can be minute, escaping detection. For this reason, macular amyloidosis is part of the differential diagnosis for the "normal skin" slide, sometimes called invisible dermatosis. Minimal epidermal changes, such as hyperkeratosis and hypergranulosis, are occasionally observed.

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Approach Considerations

It is important to note that macular amyloidosis can have a significant impact on patients' quality of life and pychopathologies owing to the appearance and location of the lesions and the pruritus severity, particularly in women.^[5]  Affected patients may benefit from psychiatric interventions.

Therapeutic modalities that have been suggested include topical and systemic medications, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers.^{[8, 9, 10]} However, evidence from randomized, controlled trials is lacking, and effictiveness is based on small studies and case reports. No standardized treatment has been established.^[11] With the growing appreciation of the importance of pruritus as the primary trigger for the deposition of amyloid, treatment modalities are often directed toward the relief of pruritus.

In more recent years, other treatments have been proposed. Microneedling appears to reduce pruritus and pigmentation in macular amyloidosis,^[27] whereas topical and intralesional tranexamic acid show mixed results, whether alone or in combination with other treatments.^{[23, 27]} Trichloroacetic acid peel may be more effective in improving the aesthetic results of macular amyloidosis relative to Nd-Yag laser and glycolic acid peel.^[28]

Fractional CO2 laser in combination with topical dimethyl sulfoxide (DMSO) 50% as well as fractional CO2 laser alone appear to be safe and effective therapeutic options for reducing pigmentation and pruritus, and for decreasing amyloid deposition.^[29] Similarly, Nd:YAG laser and Er:YAG laser appear to provide improvements in pruritis, pigmentation, and patient and clinician satisfaction.^{[30, 31]}

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Medical Care

Sedating antihistamines have been found to be moderately effective. Topical dimethyl sulfoxide (DMSO), a chemical solvent, and intralesional steroids are beneficial if combined with other modalities. DMSO has been used with moderate success, but failures have also been reported.^{[32, 33, 34]} Pandhi et al and Lim et al reported a lack of effect with DMSO treatment for cutaneous amyloidosis.^{[35, 36]}

Treatment with ultraviolet B (UV-B) light can provide symptomatic relief.^[37] Yusek et al reported improvement with transcutaneous electrical nerve stimulation.^[38] Terao et al evaluated the effects of topical tocoretinate on lichen amyloidosis and macular amyloidosis lesions. The outcome was very good for 4, good for 2, moderate for 2, and poor for 2 of 10 treated patients.^[39]

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Surgical Care

Aggressive strategies proposed for the removal of amyloid include laser vaporization, dermabrasion, and excision of individual lesions. However, lesions and pruritus usually promptly recur after these treatments. Electrodessication and curettage provided an acceptable result in one report.^[40]

In a prospective, side-by-side, controlled, clinical trial study, Ostovari et al used the Q-switched Nd:YAG laser (532 nm and 1064 nm) in 20 patients with a clinical diagnosis and pathology confirmation of macular amyloidosis. Using colorimetric score assessment and digital photographs before laser therapy and 8 weeks after treatment, they concluded that the 2 lasers are effective in reducing the degree of macular amyloidosis pigmentation, with the 532-nm laser being more effective than the 1064-nm laser.^[41] In another study, ND:YAG laser (1064 nm) treatment repeated monthly for 7 months successfully reduced hyperpigmentation in a woman with recalcitrant macular amyloidosis. However, Triluma (fluocoinolone actetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) prescribed for maintenance to prevent recurrence caused a reaction followed by recurrence of the original lesion.^[42]

Significant improvements were observed in 16 patients treated treated by fractional CO₂ using either superficial ablation or deep rejuvenation. Both modes were effective in reducing pigmentation, thickness, itching, and amyloid deposits. However, superficial ablation offered a greater reduction of pigmentation with significantly reduced pain.^[43]

A case report of pulse dyed laser (PDL) treatment in a 57-year-old man with recalcitrant macular amyloidosis who was treated with 3 sessions of PDL at 2-week intervals showed improvement after each treatment, with decreased amyloid aggregation and skin hyperpigmentation. This resulted from a decrease in collagen and dermatan sulfate synthesis similar to the mechanism behind the reduction of the size of hypertrophic scars.^[44]

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Medication Summary

The goal of pharmacotherapy is to reduce morbidity.

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Chlorpheniramine (Chlor-Trimeton)

• Dosing, Interactions, etc.

Clinical Context:  Competes with histamine or H1 receptor sites on effector cells in blood vessels and respiratory tract.

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Diphenhydramine (Benadryl, Belix)

• Dosing, Interactions, etc.

Clinical Context:  For symptomatic relief of pruritus caused by endogenous release of histamine.

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Class Summary

These agents act by competitive inhibition of histamine at the H1 receptor. They may control itching by blocking effects of endogenously released histamine.

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Dimethyl sulfoxide (Rimso-50)

• Dosing, Interactions, etc.

Clinical Context:  May help relieve symptoms. DMSO, an oxidation product of dimethyl sulfide, is an exceptional solvent possessing a number of commercial uses. Not an FDA-approved indication.

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Class Summary

This industrial solvent has been used with mixed results.

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