Amyloidosis and the Skin at a Glance
- In amyloidosis normally soluble plasma proteins are deposited in the extracellular space in an abnormal insoluble fibrillar form.
- Amyloid deposition is remarkably diverse and can be localized or systemic, rapidly lethal or incidental.
- Diagnosis of amyloidosis relies on the demonstration of pathognomonic red–green birefringence when biopsies stained with Congo red are viewed under cross-polarized light.
- Management relies on determining the type (defined by the precursor protein) and discriminating systemic from localized forms.
- Treatment of systemic disease centers on reducing the production of the fibril precursor protein and management of localized disease is usually surgical or symptomatic.
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.
Table 133-1 Classification of Systemic Amyloidosis