PubMed · 14973175
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Mary Beckman. 2004-02-18. Augmenting with amylin.. https://doi.org/10.1126/sageke.2004.7.nf19
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Among the varied and biochemically diverse group of protein folding disorders that are collectively known as the amyloidoses, AL-amyloidosis where deposits are derived from the immunoglobulin light chain fragments, is the most prevalent systemic form of the disease found in the western world. In contrast, AH-amyloidosis, resulting from the deposition of immunoglobulin heavy chains, is a rare disease with very few cases thus far reported. Both diseases primarily affect older individuals and are always associated with some form of plasma cell/B cell lymphoproliferative process. The overwhelming majority of monoclonal light chains are nephrotoxic leading to frequent renal involvement, although a wide variety of other organ systems may be involved. The most common clinical presentation is proteinuria and the disease is often diagnosed by renal biopsy. The kidneys are the most frequent site of amyloid fibril deposition in AL and light microscopic examination of Congo red stained sections is the prime means of detection. Electron microscopy may be helpful in the detection of small deposits and in the differentiation of amyloid from other types of renal fibrillar deposits. Current treatment of systemic amyloidoses depends upon the type of amyloid deposits; thus, accurate typing, using a panel of antibodies, is of paramount importance. While the differential diagnosis of amyloidoses continues to expand with increased awareness of hereditary types, currently, the main challenge is diagnosis of AL/AH with confidence. Future goals include the development of more precise and sensitive diagnostic tools. This chapter presents the pathology of AL/AH, current standards of diagnosis and the differential diagnosis. Whenever possible, the most recent references, considered as being particularly useful to clinicians and pathologists serving patients with renal amyloidosis, have been selected.
Amyloidosis is a disease in which abnormal proteins form toxic intermediates and fibrillar tissue-deposits that compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis. One-third to one-half of patients with systemic AL amyloidosis has renal involvement in the form of glomerular, vascular and interstitial deposits of amyloid causing progressive proteinuria. Less than 5% of AL patients present with renal failure requiring dialysis; patients with renal involvement usually present with fatigue, peripheral edema, proteinuria and hypoalbuminemia. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light chains, measured with the serum free light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated. The most effective treatment for systemic AL is risk-adapted melphalan with peripheral blood stem cell transplant; oral melphalan and dexamethasone is the most effective therapy for patients who are not stem cell transplant candidates although it carries a risk of myelodysplasia and leukemia. Novel therapies currently under study include thalidomide, bortezomib and lenalidomide. With therapy, a majority of patients can achieve long-term durable remissions with stabilization or recovery of organ function. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.
Under in vitro solution conditions where the native state is destabilized, many proteins present an abnormal structure and metabolism associated with a strong tendency to self-aggregation into a polymeric amyloid fibril structure, suggesting that this ability is a generic feature of the polypeptide chains. Such structures play a key role in different pathogenesis of neurodegenerative diseases such as Alzheimer, Parkinson, or Creutzfeldt-Jakob. Here, we report the formation of amyloid fibrils in the plasma protein human serum albumin under different in vitro conditions monitored using a combination of spectrophotometric and microscopic techniques. Amyloid fibril formation, therefore, is also allowed in a protein with a high degree of structural complexity. We also infer from experimental data the existence of other protein aggregated species than fibrils, some of which seem to be formed by a structural rearrangement of the proper fibrils.