Diagnosis: Amyloid A (AA) Amyloidosis
In this case, we have a patient with long-standing Crohn’s disease presenting with nephrotic range proteinuria and a decline in renal function. While all the usual suspects of nephrotic range proteinuria must be considered (see below), in any patient with chronic inflammation, AA amyloidosis, previously known as secondary amyloidosis, should be high on our differential.
Here’s a diagram which outlines many of the common etiologies of nephrotic syndrome:
AA amyloidosis is a complication of chronic inflammatory conditions. Chronic infections such as osteomyelitis or tuberculosis were historically the more common underlying etiologies, though with advances in infectious management, inflammatory arthritides, inflammatory bowel disease (such as our patient), periodic fever syndromes, and neoplasms now predominate.
AA amyloidosis falls within a group of diseases, all of which are caused by the buildup of misfolded proteins that form β-pleated sheets and deposit as fibrils, leading to organ dysfunction. There are several types of amyloidosis, based on the precursor protein (i.e. AA, monoclonal Ig light chain (AL), monoclonal Ig heavy chain (AH), transthyretin (ATTR), dialysis-related (β2-microglobulin)). The different types of amyloidosis can be confirmed about pathology using immnohistochemistry stains.
Serum amyloid A (SAA) protein, an acute phase reactant, is the culprit in AA amyloidosis. There are several forms of SAA protein, all of which are apolipoproteins, whose expression is induced in the setting of chronic inflammation by proinflammatory cytokines including interleukin (IL)-6, IL-1, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and multiple transcription factors.
The kidney is one of the most commonly affected organs with AA amyloidosis as well as AL (primary) amyloidosis and other hereditary forms (AA and AL can be most easily distinguished using immunohistochemistry stains). On pathology, the PAS stain typically reveals nodules of an amorphous, pale-staining substance – note pale staining on the PAS stain, compared to diseases like diabetic nephropathy and light chain deposition disease where nodules are composed of mesangial matrix and stain a deep magenta color. Interestingly, there are cases of AA amyloidosis in which no underlying disease is identified.
The Congo Red stain confirms a suspicion of amyloid. Immunofluorescence (IF) and immunohistochemistry (IHC) staining should be performed to confirm the presence of AA protein and exclude AL amyloidosis.
IHC for Amyloid A protein:
The crux of treating AA Amyloidosis is reducing chronic inflammation and treating the underlying disease! Patients with increased age, high circulating levels of SAA, and baseline end-stage renal failure are at high risk for mortality. Biologic agents with activity against pro-inflammatory cytokines used in the treatment of rheumatologic disorders may help prevent or even treat AA amyloidosis. Several agents to disrupt fibril formation are also under investigation.