An internal medicine resident was presenting a consult to our team on a patient with nephrotic-range proteinuria. During his presentation, he stated that he had already ruled out amyloidosis because the patient had a negative SPEP and UPEP by immunofixation.
To evaluate the validity of his statement, we need to go back to pathophysiology to review the mechanism of amyloidosis.
Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings. Under light microscopy, with hematoxylin and eosin staining, amyloid appears as an amorphous, eosinophilic, hylaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. By electron microscopy amyloid is seen to be made up largely of continuous, non-branching fibrils
. This electron-microscopic structure is identical in all types of amyloidosis.
The two major kinds of amyloidosis are:
1) Primary amyloidosis (AL) (Amyloid Light chain)
The AL protein is made up of light chains, mainly composed of λ light chains or their fragments. Its deposition is associated with certain forms of plasma cell tumors.
Diagnosis: With the use of immunochemical techniques, monoclonal immunoglobulin is found in the serum or the urine in nearly 90% of patients. If you add the serum-free light-chain assay, an abnormal result is found in 99% of patients. A biopsy of an affected organ is usually diagnostic also.
Patients with severe organ dysfunction should receive repeated cycles of Melphalan/Dexamethasone as first line therapy. Patients with less severe organ dysfunction may benefit from high Dose melphalan followed by stem cell transplant as the first line therapy. For patients with relapsed disease, the use of alternative regimens (thalidomide, lenalidomide, cyclophosphamide, or bortezomib
) is a reasonable approach that is growing in popularity.
2) Secondary amyloidosis (AA)
AA fibrils are derived by proteolysis from a larger precursor in the serum called SAA (serum amyloid–associated) protein that is synthesized in the liver under the influence of cytokines such as IL-6 and IL-1. The production of SAA protein is increased in inflammatory states as part of the “acute phase response”; therefore, this form of amyloidosis is associated with chronic inflammation. However, increased production of SAA by itself is not sufficient for the deposition of amyloid. You need to have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.
Diagnosis: Biopsies of accessory salivary glands, abdominal fat, and rectal mucosa yield positive results in 50% to 80% of patients. Kidney biopsy is positive in almost 100% of symptomatic patients.
Treatment: Treat the underlying source of inflammation. Eprodisate
is a member of a new class of compounds that inhibits polymerization of amyloid fibrils potentially slowing the decline in renal function
Getting back to the resident, I think his statement would be correct in AL (primary amyloidosis), but not valid if the patient has AA (secondary amyloidosis).
Posted by Tarek Alhamad