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Amyloidosis

Amyloidosis results from the deposition of insoluble, fibrous amyloid proteins, nearly always in the extracellular spaces of organs and tissues. The most common form of systemic amyloidosis seen in current clinical practice is AL (primary idiopathic amyloidosis, or that associated with multiple myeloma) resulting from fibril formation by monoclonal antibody light chains in primary amyloidosis and in some cases of multiple myeloma. Less than 20 percent of patients with AL have myeloma. The rest have other monoclonal gammopathies, light chain disease, or even agammablobulinemia (producing light chains, but not intact immunoglobulin). About 15 to 20 percent of patients with myeloma have

Amyloid A Amyloidosis (AA)

AA amyloidosis (secondary, reactive, or acquired amyloidosis) occurs most frequently as a complication of chronic inflammatory disease. Effective treatment of the underlying inflammatory condition has reduced incidence in developed countries. In the past in the United States, tuberculosis, osteomyelitis, and leprosy were the most

Heredofamilial Amyloidoses

Until the advent of biochemical studies, there was no generally accepted nosology for the heredofamilial amyloid syndromes. Some researchers emphasized the site of predominant organ involvement, classifying the disease as neuropathic, nephropathic, or cardiopathic amyloidosis, while others stressed the genetic aspects. With one exception, the amyloidosis of FMF, which is inherited as an autosomal recessive disorder and is an AA type of, amaloidosis, ameloidosis

Localized Or Organ-Limited Amyloidoses

Depending upon the biochemical nature of the amyloid fibril protein, instead of systemic deposition involving the cardiovascular and gastrointestinal systems along with lymph nodes, spleen, liver, kidneys, and adrenals, amyloid deposition may be limited to a single organ such as the pancreas, brain, or

Clinical Manifestations

The clinical manifestations of amyloidosis are varied and depend entirely on the biochemical nature of the fibril protein and thus the area of the body that is involved. The diagnosis of amyloidosis is usually not made until after the point of irreversible organ damage. Proteinuria is often the first symptom associated with systemic amyloidosis,

Kidney

Renal involvement may consist of mild proteinuria or frank nephrosis. In some cases, the urinary sediment may show a few red blood cells. The renal lesion is usually not reversible and in time leads to progressive azotemia and death. The prognosis does not appear to be related to the degree of the proteinuria; when azotemia finally

Heart

With respect to systemic amyloidoses, cardiac amyloidosis is common in primary (AL) and heredofamilial amyloidosis and very rare in the secondary (AA) form. With respect to localized amyloidosis, cardiac amyloidosis of the TTR type is common after 80 years of age; also atrial natriuretic factor may be present in the atria. In systemic

Liver

While hepatic involvement is common except in heredofamilial amyloidosis of the TTR type, liver function abnormalities are minimal and occur late in the disease. Portal hypertension occurs but is uncommon. Intrahepatic cholestasis has been noted in about 5 percent of patients with AL (primary) amyloidosis. Hepatomegaly is common, and AL hepatic amyloid is

Skin

Involvement of the skin is one of the most characteristic manifestations of primary (AL) amyloidosis. Other forms of

Gastrointestinal Tract

Gastrointestinal symptoms are common in all systemic types of amyloidosis. They may result from direct involvement of the gastrointestinal tract at any level or from infiltration of the autonomic nervous system with amyloid. The symptoms include those of obstruction, ulceration, malabsorption, hemorrhage, protein loss, and

Nervous System

Neurologic manifestations may include peripheral neuropathy, postural hypotension, inability to sweat, Adies's pupil, hoarseness, and sphincter incompetence. These manifestations are especially prominent in the heredofamilial

Endocrine

Amyloid may infiltrate the thyroid or other endocrine glands but rarely causes endocrine dysfunction. Local amyloid deposits almost invariably accompany medullary carcinoma of the thyroid. Amyloid is often found in the adrenal

Joints And Muscles

Amyloid can directly, although rarely, involve articular structures by its presence in the synovial membrane and synovial fluid or in the articular cartilage. In these cases it is almost always of the AL type and associated with multiple myeloma. Amyloid arthritis can mimic a number of the rheumatic diseases because it can present as a

Respiratory System

The nasal sinuses, larynx, and trachea may be involved by accumulation of AL amyloid, which blocks the ducts, in the case of the sinuses, or the air passages. Amyloidosis of the lung involves the bronchi and alveolar septa diffusely. The lower respiratory tract is affected most frequently in primary (AL) amyloidosis and in the disease

Hematopoietic System

Hematologic changes may include fibrinogenopenia, increased fibrinolysis, and selective deficiency of clotting factors. Deficient factor X seems to be due to nonspecific calcium-dependent binding to the polyanionic amyloid fibrils. Splenectomy in the patient with such a factor X deficiency can relieve the deficiency and the

Diagnosis

Amyloid fibrils are identified in biopsy or necropsy tissue sections. The systemic amyloidoses offer a choice of biopsy sites; abdominal fat aspirates or renal or rectal biopsies are often performed. Microscopically, amyloid deposits stain pink with the hematoxylin-eosin stain and show metachromasia with

Prognosis

Generalized amyloidosis is usually a slowly progressive disease that leads to death in several years, but in some instances, prognosis is improving. The average survival in most large series of AL amyloid is 12 months and in

Treatment

Rational therapy should be directed at (1) reducing precursor production, (2) inhibiting the synthesis and extracellular deposition of amyloid fibrils, and (3) promoting lysis or mobilization of existing amyloid deposits. There

While instances have been reported of remission of amyloidosis accompanying treatable infections or inflammation,

In the case of AL amyloid, the fact that immunoglobulin light chain is made by plasma cells has lead to the use of alkylating agents. However, these agents are toxic and not very effective. Recent trials have indicated that a prednisone/melphalan/colchicine program prolongs life. Hematopoietic stem cell transplantation appears promising. A novel anthracycline, iododoxorubicin, has been shown to bind to AL amyloid (similar to Congo red) in vivo and promote amyloid resorption. Only a small number of patients have received this experimental agent, but the majority have had objective improvement. Cardiac transplantation in selected cases of AL or FAPamyloidosis has

Patients with severe renal amyloidosis and azotemia have been treated by dialysis or kidney transplantation with very good outcomes. This has significantly improved the prognosis in patients whose major manifestations are

Colchicine has been shown to be effective in preventing acute attacks in patients with FMF. It has been determined from inhibition of AA amyloid deposition in the mouse model that colchicine inhibits formation of AEF. One large study has shown colchicine to be effective in prolonging life in primary (AL) amyloidosis using a life-table

The major causes of death are heart disease and renal failure. Sudden death, presumably due to arrhythmias, is