Chapter 133. Amyloidosis of the Skin

Amyloidosis is a rare condition and the exact incidence remains unclear. The overall sex and age adjusted rate per million person years was reported as 6.1 from 1950 to 1969 and 10.5 from 1970 to 1989 in the United States of America, and localized amyloidosis accounts for less than 10% of all diagnoses. Both localized and systemic forms of the disease become more frequent with age, and presentation before the age of 30 years is extremely unusual. No known racial, occupational, geographic, or other environmental factors have been implicated in the genesis of systemic amyloidosis, although there is evidence for a slight male preponderance.

Etiopathology and Pathogenesis

Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils, derived from the aggregation of misfolded protein.1,2 At least 26 unrelated proteins are known to form human amyloid fibrilsin vivo.3 The ultrastructural morphology and histochemical properties of all amyloid fibrils, regardless of the precursor protein type, are remarkably similar and fibril diffraction studies have confirmed that they all share a common core structure consisting of a cross β core and polypeptide chains lying perpendicular to the long axis of the fibril. This extremely abnormal, highly ordered conformation underlies the distinctive physicochemical properties of amyloid fibrils, including their relative stability and resistance to proteolysis. Amyloid deposits universally contain the normal plasma glycoprotein, serum amyloid P component (SAP), and heparan sulfate and dermatan sulfate proteoglycans and glycosaminoglycan chains as nonfibrillar constituents Other plasma proteins, such as apolipoprotein E, are sometimes detectable in amyloid deposits, but without the universality and abundance of SAP.

Amyloid formation in vivo occurs with both normal wild-type proteins and with genetically variant proteins. The fibrils may contain the intact amyloidogenic protein or proteolytic cleavage fragments. There is always a lag period, often of many years, between first appearance of the potentially amyloidogenic protein and the deposition of clinically significant amyloid. There are many ways of classifying amyloidosis of which the most useful is according to the deposited protein (Table 133-1). In addition, it is vital to determine whether the amyloid deposits are localized, distributed in only one tissue or organ, or deposited more widely.

Systemic AL Amyloidosis

This is the commonest type of systemic amyloidosis, accounting for more than 60% of cases. AL amyloidosis may occur in association with any monoclonal B cell dyscrasia.4 AL fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (VL) domain.5 A degree of amyloid deposition is seen in up to 15% of patients with myeloma, but the vast majority, more than 80%, of patients who present with clinically significant AL amyloidosis have very low grade and otherwise “benign” monoclonal gammopathies.

Systemic AA Amyloidosis

Reactive systemic, AA, amyloidosis is a potential complication of any disorder associated with a sustained acute phase response and the list of chronic inflammatory, infective, or neoplastic disorders that can underlie it is almost without limit.6 Although 60% of patients have inflammatory arthritis, some of the underlying diseases have cutaneous features that may facilitate diagnosis. These include: psoriatic arthritis, epidermolysis bullosa, basal cell carcinoma, chronic cutaneous ulcers, and hereditary periodic fever syndromes, particularly cryopyrin-associated periodic syndrome (CAPS) and TNF receptor associated periodic syndrome (TRAPS).7 Biopsy and postmortem series suggest that the prevalence of AA amyloid deposition in patients with chronic inflammatory diseases is between 3.6% and 5.8%, though a smaller proportion of patients have clinically significant amyloidosis. The amyloid fibrils are derived from the circulating acute phase reactant, serum amyloid A protein (SAA). SAA is an apolipoprotein of high-density lipoprotein (HDL)8 which, like C-reactive protein (CRP), is synthesized by hepatocytes under the transcriptional regulation of cytokines. A sustained high plasma level of SAA is a prerequisite for the development of AA amyloidosis, but why amyloidosis develops in only a small proportion of cases remains unclear.

Hereditary Amyloidosis

These are very rare autosomal dominantly inherited conditions. The most common cause of hereditary amyloidosis is mutations in the gene for transthyretin (TTR), which affects around 10,000 individuals worldwide, and causes familial amyloid polyneuropathy (FAP). The other hereditary systemic amyloidoses are derived from apolipoproteins AI and AII, fibrinogen A α chain, gelsolin, and lysozyme.9

Localized Amyloidosis

Localized amyloid deposition is not uncommon, although often undiagnosed, and reportedly accounts for 9.3% of all amyloidosis.10 It results either from local production of fibril precursors or from properties inherent to the particular microenvironment, which favor fibril formation of a widely distributed precursor protein. The vast majority of deposits are AL in type, and symptomatic deposits occur most frequently in the eye, skin, gastrointestinal, respiratory, or urogenital tracts.8 They are often associated with extremely subtle focal monoclonal B cell proliferation confined to the affected site and surgical resection of these localized “amyloidomas” can sometimes be curative. Symptomatic apparently localized amyloid deposits can rarely be manifestations of systemic disease and patients should always be fully investigated to exclude more generalized amyloid deposition.11 Progression from localized to systemic amyloidosis is very rare. In lichen and macular amyloidosis, the fibrils are derived from proteins released from apoptotic keratinocytes. The etiology is not entirely clear but the association with other pruritic conditions suggests that mechanical factors associated with chronic scratching and skin friction are probably crucial.12

Approach to Patient Algorithm

(See Fig. 133-1)

History

In the majority of patients with systemic amyloidosis the presentation is nonspecific, and as a result amyloid is often an unexpected finding on biopsy of an affected organ.

AL Amyloidosis

AL amyloid usually presents in patients over the age of 50 years, although it can present in very young adults.4 In the majority of cases, the underlying plasma call clone is not detected prior to presentation with amyloid-related organ dysfunction. Clinical manifestations are extremely variable since almost any organ other than the brain can be directly involved.13 Although certain clinical features such as macroglossia and periorbital ecchymoses are very strongly suggestive of AL amyloidosis (Table 133-2), and multiple vital organ dysfunction is common, many patients present with nonspecific symptoms such as malaise and weight loss.

AA Amyloidosis

AA amyloidosis can present anytime between childhood and old age with a median age at presentation of 48 years in the United Kingdom. Almost 95% of patients have a clinically overt previously diagnosed chronic inflammatory disease such as rheumatoid or one of the other inflammatory arthritides, chronic sepsis usually bronchiectasis, complications of paraplegic conditions, or drug abuse. It is slightly more common in men. Although the disease can develop very rapidly, the median latency between presentation with a chronic inflammatory disorder and clinically significant amyloidosis is almost two decades. It usually presents with proteinuria and subsequently progressive renal dysfunction, often accompanied by nephrotic syndrome.6

Hereditary Amyloidosis

The presentation of hereditary amyloidosis varies depending on the variant protein, mutation, and even within kindreds.14,15 Severe progressive peripheral and/or autonomic neuropathy is the major feature of hereditary TTR amyloidosis (FAP), but cardiac involvement is also common. ApoAI amyloidosis sometimes causes neuropathy, but this is not a feature of the other hereditary types, which typically involve the viscera. All the amyloidogenic mutations are dominant, but they are variably penetrant and therefore a family history may be absent.

Cutaneous Lesions

Systemic AL Amyloidosis

Cutaneous manifestations are common in systemic amyloidosis, particularly the AL type, and are reported in up to 40% of patients.4 The lesions usually reflect capillary infiltration and fragility with petechiae and purpura, particularly affecting the eyelids, beard area, and upper chest (Fig. 133-2A).16 Xanthomatous papules or plaques are also frequently observed and amyloidotic hyperpigmented keratotic lesions have been reported occasionally. Other rare cutaneous lesions include scleroderma-like changes (Fig. 133-2B), alopecia, and nail dystrophy (Fig. 133-2C). Bullous amyloidosis affecting the skin and mucosa has been described.17 The bullae can be intradermal or subepidermal and present as tense, often hemorrhagic blisters. Generalized infiltration of cutaneous tissues can frequently cause the appearance of skin thickening with loss of facial wrinkles and can limit mouth opening.

Hereditary Amyloidosis

Lysozyme amyloidosis frequently causes petechial eruptions (Fig. 133-3) and apolipoprotein AI amyloidosis can also manifest as yellowish infiltrated plaques and acanthosis nigricans-type lesions.15,18 Cutaneous lesions in FAP seem to be largely due to the peripheral neuropathy. They manifest as xerosis in 82%, seborrheic dermatitis in 22%, trauma or burn lesions in 20%, neuropathic ulcers in 14%, and onychomycosis in 10.5% of patients.19

Localized Cutaneous AL Amyloidosis

As in systemic AL amyloidosis, the fibrils are derived from N-terminal cleavage fragments of monoclonal immunoglobulin light chains. The lesions are those seen in systemic AL amyloidosis and present as single or more frequently multiple lesions anywhere on the skin.20 In our series of 20 patients; 35% had indolent papular, nodular, or xanthomatous lesions (Fig. 133-4), 20% purpuric rash, 20% pruritus, 15% local bleeding, and 10% localized swelling. In only 15% of cases were the lesions painful.21

Macular Amyloidosis and Lichen Amyloidosis

Macular and lichen amyloidosis are variants of a single pathology in which the amyloid fibrils are derived from galectin-7 following epidermal damage and keratinocyte apoptosis.22 They are usually idiopathic or friction related, but have been reported in association with connective tissue diseases (primary biliary cirrhosis, systemic lupus erythematosus and Sjögren's syndrome)23 and in a few kindreds with pachyonychia congenita24 or multiple endocrine neoplasia type 2a.25

Macular amyloidosis usually affects the upper back and limbs and can persist for many years. The rash is pruritic in the great majority of cases and consists of small brownish macules distributed in a rippled pattern. There may be a female preponderance,26 and it is more common among Central and South Americans, Middle Easterners, and non-Chinese Asians. Amyloid deposits usually are confined to the papillary dermis and do not involve blood vessels or adnexal structures. Early lesions contain small, multifaceted, amorphous globules within the papillae, and these are missed easily without the use of special stains. Later lesions show globules that coalesce, expand the papillae, and displace the rete ridges laterally. Lichen amyloidosis is the commonest type of cutaneous amyloidosis in Chinese individuals and usually affects adults.12,27 It is clinically characterized by an intensely pruritic eruption of multiple discrete hyperkeratotic papules that may coalesce to form gray–brown plaques that are distributed on the extensor surfaces of the lower extremities. There may be spread to the extensor aspects of the arms and the trunk. Histologically, the deposits are very similar to macular amyloid but slightly larger and are accompanied by irregular acanthosis and hyperkeratosis of the overlying epidermis.

Other Localized Cutaneous Amyloidosis

Deposition of insignificant microscopic amounts of amyloid in relation to a variety of cutaneous lesions is well recognized. Reported predisposing conditions include intradermal nevi, sweat gland tumors, pilomatrixoma, dermatofibroma, seborrheic keratosis, solar elastosis, photosensitive annular elastolytic giant cell granuloma, actinic keratosis, porokeratosis of Mibelli,28 Bowen's disease, and basal cell carcinoma and following PUVA therapy.

Anosacral Cutaneous Amyloidosis

This is a rare syndrome described in Japanese and Chinese males in which pigmented macules and glossy hyperkeratotic lesions radiate out from the anus.29

Insulin-Derived Amyloidosis

A rare complication of long-term insulin use in diabetics is formation of insulin-derived amyloidomas at sites of repeated insulin injection. These can be confused with tumors.30

Familial Primary Localized Cutaneous Amyloidosis

This very rare autosomal dominant disorder is characterized by chronic pruritus from childhood or early teenage-years and hyperkeratotic papules and/or hyperpigmented macules on the limbs or trunk. It is relatively common in Southeast Asia and the amyloid appears to be confined to the skin. It is associated with mutations in the OSMR and IL31RA genes, related genes which are members of the interleukin-6 cytokine receptor family.31

Related Physical Findings

Systemic AL Amyloidosis

Systemic AL amyloidosis is protean in its manifestations (Table 133-2, Fig. 133-5) and can cause signs in any organ system except the brain.

Systemic AA Amyloidosis

This presents with nephrotic syndrome in just under half of patients. Clinically, splenomegaly is frequent and hepatomegaly is detected in 10% of cases. Cardiac involvement and peripheral or autonomic neuropathy are very rare.

Hereditary Amyloidosis

The physical findings depend on the variant protein and specific mutations and may vary even within individual families.

All patients should have comprehensive assessment of renal and liver function, including blood tests, and quantification of creatinine clearance and proteinuria.32 A search should be made for evidence of an underlying plasma cell dyscrasia by serum and urine electrophoresis and immunofixation.33 In suspected amyloid of AL type, a bone marrow aspirate and trephine are usually mandatory. Where available serum assays of potential fibril precursor proteins; free immunoglobulin light chains in AL type and SAA in AA amyloidosis are very valuable.34

Histology

The identification of amyloid depends on the pathognomonic redgreen dichroism observed when tissue stained with the aniline dye Congo red is viewed under cross-polarized light (Fig. 133-6).35 This optical effect is produced by alignment of the dye molecules along the fibrils. Binding of thioflavin T usually corresponds with Congo red birefringence but is less specific. Congo red staining for amyloid is not a very sensitive test and requires the presence of an adequate amount of amyloid, use of sufficiently thick tissue sections, technically correct staining and visualization procedures, and adequate observer experience. In negatively stained electron microscopy amyloid fibrils are usually about 10 nm in diameter, straight, rigid, nonbranching, of indeterminate length, and composed of twisted protofibrils.

Positive histology for amyloid must be followed up by immunohistochemistry to determine the fibril protein type.11 Suitable antibodies are widely available but, although immunohistochemistry usually yields definitive results in AA amyloidosis, it is frequently not diagnostic with AL deposits. Expertise in the immunohistochemical typing of hereditary amyloid is restricted, and definitive immunohistochemical typing of amyloid deposits cannot always be achieved.36 Direct sequencing of extracted fibrils permits identification of the amyloid type as does laser microdissection and mass spectrometry37 however, these techniques are generally only available in a research setting.

Genetic Sequencing

Amyloidogenic mutations should be sought in all patients in whom the amyloid type remains undetermined as hereditary amyloidosis accounts for a substantial number of these cases.38

Imaging Amyloid In Vivo

SAP Scintigraphy

SAP is a highly conserved, invariant plasma glycoprotein of the pentraxin family that becomes specifically and highly concentrated in amyloid deposits of all types as a result of its calcium-dependent binding to amyloid fibrils. Radiolabeled SAP scintigraphy can be used for diagnosis and quantitative monitoring of amyloid deposits.39 This safe noninvasive method provides information on the presence, distribution and extent of visceral amyloid deposits, and serial scans monitor progress and response to therapy (Fig. 133-7). Unfortunately, the method is not informative about amyloid deposition in the moving heart and is not commercially available.

Cardiac Imaging

Cardiac amyloidosis is best evaluated by a combination of echocardiography and ECG.40 Two-dimensional Doppler echocardiography classically reveals concentric biventricular wall thickening with a restrictive filling pattern. Amyloid causes diastolic dysfunction with well-preserved contractility until a very late stage. The ECG may be normal in patients with substantial cardiac amyloidosis, but in advanced disease commonly shows small voltages, pathological “Q” waves (pseudoinfarct pattern). Recent developments in magnetic resonance imaging can also contribute to assessment of the severity of cardiac amyloidosis,41 as can serum assays of the cardiac biomarkers, N-terminalpro-BNP42 and troponin T.43

(See Box 133-1)

AL Amyloidosis

Restrictive cardiomyopathy is the presenting feature in up to one-third of patients and ultimately the cause of death in one-half.44 Renal involvement is frequent and presents with proteinuria and progressive renal impairment.45 Gut involvement can cause motility disturbances (often secondary to autonomic neuropathy), malabsorption, perforation, hemorrhage, or obstruction.46 Peripheral neuropathy occurs in one-fifth of cases and typically presents with a painful sensory polyneuropathy followed later by motor deficits.47 Autonomic neuropathy causing orthostatic hypotension, impotence, and gastrointestinal disturbances may occur in isolation or with a peripheral neuropathy.

AA Amyloidosis

Progressive renal failure and nephrotic syndrome are the usual complications in AA amyloidosis. Although splenic amyloid deposits are almost universally present in AA type, they are usually asymptomatic. Hepatic involvement and autonomic neuropathy are well recognized, but usually occur very late in the disease. Cardiac amyloidosis occurs in less than 2% of cases.6

Hereditary Amyloidosis

Familial polyneuropathy causes progressive peripheral and/or autonomic neuropathy and cardiomyopathy and in some cases visual loss due to vitreous amyloid deposits.14 Apolipoprotein AI amyloidosis can cause peripheral neuropathy but, in common with Apolipoprotein AII, lysozyme, and fibrinogen A α chain types renal or hepatic amyloidosis is typical.8 Gelsolin-related amyloidosis causes a characteristic clinical picture of corneal lattice dystrophy and cranial neuropathy.

Localized Cutaneous Amyloidosis

This only produces local complications usually in the form of pruritus or bleeding and is rarely painful.

Although recent advances have greatly extended median survival, the prognosis of systemic amyloidosis remains grave.

AL Amyloidosis

Prognosis is particularly poor in AL disease as the diagnosis is often made late, when patients already have substantial visceral and/or neural involvement. Indeed, a 5-year survival of approximately 10% and a 10-year survival of less than 5% have been reported for the AL type,4 although more recent series suggest a median survival of 40 months.48 Most affected individuals eventually die of heart failure, uremia, or autonomic failure.

AA Amyloidosis

The prognosis of AA amyloidosis depends on the degree of renal dysfunction at presentation and whether the underlying chronic inflammatory disease can be effectively suppressed, so that the plasma SAA is maintained within the normal healthy range. In our cohort of 374 patients, median survival was just over 11 years and a third of patients developed end-stage renal failure, which was the major cause of death.6

Hereditary Amyloidosis

In FAP median survival is 10–15 years without liver transplantation.49 Death is from progressive neuropathy and or cardiomyopathy. In the other hereditary amyloidosis, organ failure either renal or hepatic is the major cause of mortality, but the time to reach end-stage organ failure is very variable.

Localized Cutaneous Amyloidosis

These skin-limited conditions are not usually associated with any increase in mortality.

Treatment of all types of amyloidosis is focused on measures that can reduce the supply of the respective amyloid fibril precursor protein, while supporting or replacing compromised organ function. Under favorable circumstances, this results in regression of existing amyloid deposits, preservation or recovery of the function of amyloidotic organs, and much improved patient survival. Such treatment requires precise identification of the amyloid fibril type through immunochemistry, DNA sequencing and direct fibril sequencing. Monitoring of therapeutic efficacy and rational decisions about further treatment options are enhanced by the recent availability of routine assays for circulating free immunoglobulin light chains in AL amyloidosis and SAA in AA type.

AL Amyloidosis

Treatment in AL amyloidosis aims to suppress the proliferation of the underlying B-cell clone and, therefore, production of the amyloidogenic monoclonal immunoglobulin. This is not without problems50: chemotherapy regimens are based on those used in multiple myeloma, but the majority of plasma cell dyscrasias in AL patients are low grade and may be less chemosensitive. Diagnosis can be delayed, and many patients have advanced multisystem disease, which limits their options for chemotherapy. Regression of amyloid is a gradual process that may not lead to measurable clinical improvement or recovery of organ function for many months, or even years after successful suppression of the causative plasma cell dyscrasia.48 Mobilization of amyloid from the heart is much slower than from the liver or kidneys, and many patients with cardiac or multisystem dysfunction do not live long enough to benefit from chemotherapy, even when it has suppressed their clonal disease. Nonetheless, many patients with AL amyloidosis do benefit substantially from chemotherapy. Prolonged low-intensity cytotoxic regimes such as oral melphalan and prednisolone are beneficial in about 20% of patients. Although there have been few comparative clinical trials,51 chemotherapy regimens containing melphalan and dexamethasone, cyclophosphamide, thalidomide and dexamethasone,52 or velcade,53 and autologous peripheral blood stem-cell transplantation are almost certainly much more effective.54 Very rigorous patient selection for high-dose chemotherapy is essential because the procedure-related mortality is extremely high in individuals with multiple organ involvement.55

AA Amyloidosis

Treatment of the primary inflammatory conditions responsible for AA amyloidosis reduces amyloid levels, dramatically improves survival, and is associated with arrest of amyloid deposition and frequently regression of deposits. The new biological drugs targeting key cytokine mediators of inflammation potently suppress the acute phase response in many patients with inflammatory arthritis, Crohn's disease, and some hereditary periodic fevers.56 Colchicine is the treatment of choice to prevent AA amyloidosis in familial Mediterranean fever.

Hereditary Amyloidosis

At present, apart from transplantation to replace failed organs and liver transplantation to reduce production of amyloidogenic proteins that are synthesized by the liver, only symptomatic treatment is available for hereditary systemic amyloidosis. The liver is the source of plasma TTR, and over 1,000 liver transplants have been performed for treatment of hereditary TTR amyloidosis since this “surgical gene therapy” approach was introduced in 1991.49 In younger patients carrying the common Val30Met mutation, the outcome is generally good, with arrest of neuropathy and regression of visceral amyloid, but the outcome in patients with other mutations has been less successful.57

Novel Treatments for Systemic Amyloidosis

Better understanding of the mechanisms underlying amyloid formation has led to the development of novel treatment strategies aimed at inhibiting fibrillogenesis or destabilizing existing amyloid deposits.58,59 Preliminary work in mice has demonstrated that antiamyloid antibodies were effective in clearing cutaneous amyloid deposits without the necessity of an immune response.60

Localized Cutaneous AL Amyloidosis

Small localized amyloid deposits can be removed surgically or by laser if they are cosmetically disfiguring or bleeding, but there is a very high rate of local recurrence. The possibility that systemic chemotherapy may be of any benefit in localized AL amyloidosis has not been systematically tested.

Macular and Lichen Amyloidosis

Chronic friction is a major etiological factor in these and treatment modalities should be directed toward the relief of pruritus in these conditions. Sedating antihistamines have been found to be moderately effective and intralesional steroids are beneficial if combined with other modalities. Topical dimethyl sulfoxide (DMSO), a solvent, has been used with modest success at best61 but is often unacceptable to patients due to the smell. Treatment with ultraviolet B (UVB) light can provide symptomatic relief.62 There is one report of improvement following treatment with 0.1% topical tacrolimus ointment.63 Systemic cyclosporine or retinoids may also be beneficial.64