The Clinical Spectrum of Amyloidosis

*Aswanth Reddy, Enrique Ballesteros and Jonathan Scott Harrison*

## **Abstract**

Amyloidosis is a group of disorders that share a common pathobiology: in each case, a protein that exhibits misfolding is deposited in one or multiple organs leading to disruption in organ function. These amyloid proteins are recognized as amorphous pink material in Hematoxylin and Eosin staining, with confirmation by staining with Congo red and yellow or green birefringence under polarized light microscope. To date at least 36 different types of amyloid proteins have been identified. Worldwide, AA amyloidosis is the most common type, and this occurs secondary to chronic inflammatory disease states—such as chronic infections and rheumatological disorders. In western countries, the incidence of AA amyloidosis is decreasing, and AL is the most common type of amyloidosis, characterized by amyloid due to light chain deposition. ATTR amyloidosis, which can be either hereditary or acquired, is a unique variant of systemic amyloidosis that results from mutations in the transthyretin (TTR) gene. Our review will focus on clinical features of the most common systemic amyloidosis, with a detailed review on evaluation and management of AA, AL and ATTR amyloidosis.

**Keywords:** AA amyloidosis, AL amyloidosis, ATTR amyloidosis

### **1. Introduction**

Amyloidosis is a group of disorders that share the common feature of deposition into tissues of any one of a number of different proteins. The uniform underlying pathobiology is the finding that in each case, the protein—termed amyloid—deposited into the target organ has undergone abnormal three-dimensional folding. The abnormal folding of the peptide results in accumulation in tissues as microfibrillary structures. The deposition of amyloid protein, regardless of which specific protein forms the amyloid, results in disruption in the function of the organ in which the amyloid protein is deposited. The common histopathologic feature of all amyloidosis is the finding, by light microscopy, of amorphous protein in one or more organs, typically initially recognized upon histologic review of a biopsy, as an amorphous pink material on Hematoxylin and Eosin staining (**Figure 1**). Per the International Society of Amyloidosis 2016 nomenclature guidelines, amyloid fibrils must exhibit affinity for the histologic stain Congo red, showing green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. At least 36 different proteins can undergo abnormal folding and result in deposition of amyloid, causing clinical disease. It is conventional to describe a

#### *Amyloid Diseases*

particular amyloid protein as "Amyloid Protein AX," where the X is a suffix to the designation, based on the identity of the amyloid protein. The more commonly encountered subtypes are, for example Amyloid Protein AL, Amyloid Protein AA, and Amyloid Protein ATTR, as discussed below. This chapter is an overview of the different categories of amyloidosis, with a focus on the clinical features, prognosis, and management of focal or systemic amyloidosis. Symptoms depend on the type and amount of amyloid protein, and are often variable. The manifestations depend on the identity of the underlying protein that forms the amyloid fibrils, the burden of amyloid, and the organs involved, as well as comorbidities of an individual patient (see **Table 1**).

#### **Figure 1.**

*Photomicrographs of a lymph node biopsy with AL amyloidosis. Panel A: 10× magnification of a left axillary lymph node biopsy stained using Hematoxylin and Eosin, demonstrating amorphous pink material typical of amyloid infiltration. White areas are fat that has been leached from the tissue in processing. Panel B: 10× magnification of the same lymph node stained using Congo red, viewed by light microscopy.*


#### **Table 1.**

*Clinical manifestation of systemic amyloidosis.*
