Amyloidosis

“Amyloidosis” describes a group of diseases characterized by extracellular (and rarely intracellular) deposition of “amyloid”; material composed of protein fibrils with a typical X-ray diffraction pattern and affinity for the dye Congo red with resulting birefringence on polarization. Other components of amyloid deposits include glycosaminoglycans, apolipoprotein E and serum amyloid P-component (1, 2).

There are numerous types of amyloid and all are designated with “A” plus a suffix indicating the amyloidogenic precursor protein (1-5). For instance, AL-amyloid is used to designate a fibril protein derived from immunoglobulin light (L) chains, while AApoAI-amyloid describes the fibril protein derived from apolipoprotein A-I. More common types of amyloid include AL (light chain derived), AH (heavy chain derived) Aß2M (ß2-microglobulin derived), ATTR (Transthyretin derived) and AA (Serum AA derived) (Table 1). The type of amyloid can usually be determined by immunohistochemical staining of tissue sections; however, the composition of the amyloid protein can also be determined by tandem mass spectrometry (6).

Renal involvement in amyloidosis is common. Patients usually present with fatigue and weight loss, and are often found to have renal insufficiency and proteinuria. Within the kidney, amyloid most commonly deposits within glomeruli but may also be present within artery walls, the renal interstitium and rarely as a component of tubular casts (5, 7). The degree of renal involvement may be variable and small amounts of amyloid can be missed if the tissue is not carefully examined.

Amyloid deposits within the glomerular mesangium and often extends into the capillary wall where it may form subepithelial “spicules” that extend perpendicular to the outer capillary wall and mesangial regions. Amyloid deposits are generally silver negative or may be weakly stained, however are on occasion, silver positive. The capillary wall “spicules” are typically silver positive and are distinctive for amyloid. Amyloid deposits also tend to be negative or weakly stained on the PAS stain (Figure 1). The amyloid deposits, which are orange on the congo red stain, become green on polarization (referred to as “apple green” birefringence), a feature that is diagnostic (Figure 2).

Most AL-type amyloid is lambda light chain associated, however may show kappa light chain restriction or be associated with a heavy chain (Figure 3). Immunohistochemical stains performed on paraffin-embedded tissue may be useful in determining the type of amyloid, particularly if no light or heavy chain restriction is identified on immunofluorescence (Figure 4).

Amyloid fibrils, regardless of the precursor protein, are typically 8-12 nm in diameter and are non-branching. This feature is identifiable ultrastructurally (Figure 5).

Once a tissue diagnosis of amyloidosis is established and the type of amyloid determined, treatment can commence. Patients suspected of having AL amyloid on renal biopsy must be evaluated for the presence of a plasma cell dyscrasia by bone marrow biopsy and serum and urine immunfixation electrophoresis to detect a monoclonal light chain (8). Patients with AA amyloidosis are generally treated for the underlying inflammatory disease in order to reduce the production of SAA. Orthotopic liver transplantation is the definitive treatment for TRR amyloidosis since the liver is the site of TTR synthesis. Combined liver and kidney transplantation has been performed in individuals with fibrinogen Aa amyloidosis with satisfactory outcomes (8).

References:

1. Westermark P, Benson MD, Buxbaum JN et al. A primer of amyloid nomenclature. Amyloid 14(3):179-183, 2007.
2. 2. Westermark P, Benson MD, Buxbaum JN et al. Amyloid: Toward terminology clarification. Report from the Nomenclature committee of the International Society of Amyloidosis. Amyloid 12(1):1-4, 2005.
3. Bellotti V, Nuvolone M, Giorgetti S et al. The workings of the amyloid diseases. Annals of Medicine 39:200-207, 2007.
4. Picken MM. New insights into systemic amyloidosis: The importance of diagnosis of specific type. Curr Opin Nephrol Hypertens 16:196-203, 2007.
5. Dember KM. Amyloidosis-Associated Kidney Disease. J Am Soc Nephrol 17:3458-3471, 2006 Murphy CL, Wang S, Williams T, Weiss DT, Solomon A. Characterization of systemic amyloid deposits by mass spectrometry. Methods Enzymol 412:48-62, 2006.
6. Melato M, Falconieri G, Pascali E, Pezzoli A. Amyloid casts within renal tubules: a singular finding in myelomatosis. Virchows Arch A Pathol Anat Histol 387(2):133-145, 1980.
7. Sanchorawala V. Light-Chain (AL) Amyloidosis: Diagnosis and Treatment. Clin J Am Soc Nephrol 1:1331-1341, 2006.

Date of last revision: September 2009