Amyloids: A Basic Primer
by Alan Cocchetto, Medical Director ©2004
What are amyloidoses?
Amyloidoses represent a spectrum of diseases characterized by the aggregation and deposition of amyloid. An amyloid is a universally used term that refers to abnormal intracellular or extracellular deposition of proteins as fibrils. Amyloid fibrils may be deposited in a variety of organs including brain, liver, heart, kidney, pancreas, nerve and other tissues as a consequence of certain inherited and acquired disorders. Examples of these disorders include Alzheimer's disease, Parkinson's disease, multiple myeloma, neuropathies, cardiomyopathies, monoclonal plasma cell dyscrasias, adult-onset diabetes, chronic inflammation, bovine spongiform encephalopathy and Creutzfeld-Jacob disease.
What are the characteristics of these amyloid proteins?
An amyloid is not a uniform deposition. In fact, it may be composed of unrelated proteins. Several proteins that have been identified as capable of forming amyloid in human diseases include immunoglobulin light chains, serum amyloid A protein, beta 2-microglobulin, transthyretin, gelsolin, procalcitonin, beta-amyloid protein and prion protein. Although these proteins are unrelated, the fibrils which they form have common biological properties. These properties include possessing a beta-pleated sheet secondary structure; they form insoluble aggregates; they exhibit green birefringence after dye staining; and they possess a characteristic unbranching fibrillar structure when observed under electron microscopy.
How are amyloidoses characterized?
Typically, amyloids have been classified based on their clinical features into categories that include primary amyloid, secondary amyloid, familial amyloid, and isolated amyloid. A primary amyloid is an amyloid that appears without any preceding disorder. A secondary amyloid appears as a complication or result of a previously existing disorder. For example, patients with rheumatoid arthritis, osteoarthritis, or tuberculosis can develop a secondary amyloidosis. The familial form of amyloid is found in patients diagnosed with genetically inherited forms of amyloid whereas an isolated amyloid only tends to involve a single organ system. For example, Type-II diabetic patients have isolated amyloid deposits in the pancreas restricted to the beta cells in the islets of Langerhans.
As medical research evolves however, amyloids are also being classified according to the major protein type that is found associated with the underlying disorder. As mentioned above, some of these major proteins include the AA amyloid, AL amyloid, transthyretin, beta 2-microglobulin, procalcitonin, beta-amyloid protein and the prion PrP protein. For example, the AA amyloid is commonly found in a host of seemingly unrelated disorders that include chronic inflammation as well as various forms of malignancy.
Why are amyloids of potential significance to CFS patients?
The AL amyloid usually occurs secondary to multiple myeloma, or B-cell type malignancies, as well as other plasma cell dyscrasias. The AL amyloid is usually due to the deposition of the variable region of immunoglobulin light chains, either lambda or kappa chain, but the entire light chain may also be present. This description is particularly intriguing and of significance to patients with chronic fatigue syndrome due to an early medical observation made by Dr. Paul Cheney and Dr. Daniel Peterson in Lake Tahoe patients. As reported in Osler's Web in 1985, Drs. Cheney and Peterson used a then new medical test for spotting lymphomas at a presymptomatic stage. They utilized a test, developed by Harvard scientists, to monitor the progression of B-cell lymphomas since various uncommon tumors had been spotted in some of their CFS patients. The uniqueness of the test was that the measurements are done on a single-cell basis or a per-cell basis thus enabling scientists to detect very small numbers of circulating abnormal cells. The test that Drs. Cheney and Peterson utilized is known as the kappa-lambda light chain or clonal excess assay. It uses flow cytometry to quantitate cell abnormalities.
It is a test that is commonly used now by oncologists for suspicions of multiple myeloma. What Drs. Cheney and Peterson learned was that 25% of their CFS patients tested positive for light chain clonal excess.
Since that time period, the NCF has found that many of our own CFS patients have tested positive for this assay as well and we believe that an important relationship exists regarding an amyloidosis. In a previous Forum, the NCF pointed out the fact that in September 2003 the CDC
announced their finding of an amyloid in CFS patients although they have yet to classify it. As you may recall, last summer the NCF provided Dr. Hokama a research grant to examine CFS samples for various amyloid proteins. The NCF has recently been informed that a manuscript has been submitted by Dr. Hokama and his team and we are anxiously awaiting formal publication of their data regarding their findings on their preliminary amyloid research!
Why is all of this important to CFS patients?
Amyloid deposition is generally an irreversible pathologic process. In most instances, the constant accumulation of amyloid fibril proteins leads to progressive organ dysfunction and eventual death. This is why the NCF had funded research into amyloids and why we subsequently requested patient tissue samples.
The diagnosis of amyloid deposition is almost exclusively done by the morphologic examination of tissue material taken from biopsy samples or autopsied organs. Positive staining with a special dye and exhibition of green birefringence in polarized light are generally accepted principles, which suggest the deposition of amyloid in the examined sample. The finding of fibrils by electron microscopy in biopsies or tissues under examination confirms the diagnosis of amyloidosis. Ongoing research has revealed that different proteins can be deposited as amyloid fibrils. Approximately 20 different proteins have been discovered as constituents of amyloid so far. It is of decisive importance for the prognosis and therapy of amyloid related diseases to discover the very nature of the proteins in the deposits.
The National CFIDS Foundation has demonstrated that it is fully committed to understanding the underlying pathologic process involved in this disease. It is through your continued financial support that appropriate research be funded to resolve these important medical issues.
Mechanisms of Disease: Molecular Mechanisms of Amyloidosis; Merlini GM, Bellotti V;
NEJM 349 (6): 583-596; 2003
Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic; Johnson H;
Crown Publishers, 1996
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