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Diagnosis:

Amyloidosis

Systemic amyloidosis has been classified as 1.) primary systemic amyloidosis, with no evidence of preceding or coexisting disease, paraproteinemia, or plasma-cell dyscrasia; 2.) amyloidosis associated with multiple myeloma; or 3.) secondary systemic amyloidosis associated with coexisting chronic inflammatory or infectious conditions.

In the primary amyloidosis there are deposition of insoluble monoclonal immunoglobulin (Ig) light (L) chains or L-chain fragments in various tissues, including muscles, connective tissues, blood vessel walls, and peripheral nerves. The amyloid is made by plasma cells in the bone marrow. These L-chains are secreted into the serum. Unlike the normal L-chain and the usual form seen in patients with myeloma, these L-chains are unique in that they undergo partial lysosomal proteolysis within macrophages, and they are extracellularly deposited as insoluble amyloid filaments attached to a polysaccharide. Sometimes, instead of an intact L-chain, this amyloid has the amino-terminal fragment of an L-chain.

In 1838, Mathias Schleiden (a German botanist) coined the term amyloid to describe the normal amylaceous constituent of plants. In 1854, Rudolf Virchow used the term amyloid. Virchow described its reaction with iodine and sulfuric acid, which, at the time, was a marker for starch; thus, the term amyloid or starchlike is used. Some 70 years after Virchow's description, Divry and associates recognized that the amyloid deposits showed apple-green birefringence when specimens stained with Congo red were viewed under polarized light. This observation remains the sine qua non of the diagnosis of amyloidosis. In 1959, with the use of electron microscopy, Cohen and Calkins first recognized that all forms of amyloidosis demonstrated a nonbranching fibrillar structure. Electron microscopy remains the most sensitive method for recognizing the disorder. (Nyirady J, Schwartz RA. Amyloidosis, primary systemic. e-medicine: (June 13, 2006)

About 23 different unrelated proteins are known to form amyloid fibrils in vivo, which share a pathognomonic structure although they are associated with clinically distinct conditions. Systemic amyloidosis, with amyloid deposits in the viscera, blood vessel walls, and connective tissue, is usually fatal and is the cause of about one per thousand deaths in developed countries (Pepys MB. Amyloidosis. Annu Rev Med. 2006;57:223-41. [PubMed link]).

The final pathway in the development of amyloidosis is the production of amyloid fibrils in the extracellular matrix. The process by which precursor proteins produce fibrils appears to be multifactorial and differs among the various types of amyloidosis.

The diagnosis depends on the demonstration of amyloid deposits in tissue. The organs most commonly involved are the kidneys or heart, either individually or together (Murtagh, 2005). Autonomic and sensory neuropathies are relatively common features.

Amyloid deposition in the kidney can involve not only glomeruli and vessels, but also the interstitium and the tubular basement membranes, giving rise to several different morphological pictures. There are cases of only minimal glomerular deposition, expressed by small mesangial nodules. These very early cases need a careful demonstration of the few mesangial amyloid fibrils by electron microscopy. In some cases, not only a more evident mesangial deposition, but also an initial involvement of the capillary walls can be detected. In more advanced cases, huge deposits completely alter the glomerular strucutre. When the deposits are massive, a “nodular form” is commonly found and has to be differentiated from other nodular glomerulonephritis, such as diabetic GS, light chain deposition disease and idiopathic MPGN. Amyloid specific stainings have to be performed in order to achieve a correct diagnosis.

In the present case, the nephrotic syndrome associated to concentric ventricular left hypertrophy with a thick septum suggests a systemic disease and/or a deposit disease. In our patient, serum protein electrophoresis and bone marrow study were normal, then, plasmatic cell dyscrasia was not found. The final diagnosis was primary systemic amyloidosis. In some cases is possible to find plasmatic or limphoproliferative disease in the disease course.

See the chapter [Amiloidosis, mieloma múltiple, enfermedad por depósitos de cadenas ligeras... ] (only in spanish).

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Bibliography

• Pepys MB. Amyloidosis. Annu Rev Med. 2006;57:223-41. [PubMed link]
• Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, Merlini G, Saraiva MJ, Sipe JD; Nomenclature Committee of the International Society of Amyloidosis. Amyloid: toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid. 2005 Mar;12(1):1-4. [PubMed link]
• Palma CL, Grunholz D, Osorio G. [Clinical features of patients with the pathological diagnosis of amyloidosis] Rev Med Chil. 2005;133:655-61. (Spanish). [PubMed link] [Free full text].
• Hazenberg BP, van Gameren II, Bijzet J, Jager PL, van Rijswijk MH. Diagnostic and therapeutic approach of systemic amyloidosis. Neth J Med. 2004;62:121-8. [PubMed link] [Free full text]
• Ferrario F, Rastaldi MP. Renal amyloidosis (part I). RENAL PATHOLOGY LEARNING. [Go to Web site]
• Ferrario F, Rastaldi MP. Renal amyloidosis (part II). RENAL PATHOLOGY LEARNING. [Go to Web site]
• Nyirady J, Schwartz RA. Amyloidosis, primary systemic. e-medicine: (June 13, 2006). [Go to Web site]

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