Information on the following diseases can be found in the Related Disorders section of this report:

• Multiple Myeloma
• Hodgkin's Disease
• Lymphoma Medullary carcinoma of the thyroid
• Whipple's Disease
• Crohn's Disease
• Osteomyelitis
• Rheumatoid Arthritis
• Ankylosing Spondylitis
• Reiter's Syndrome
• Psoriatic Arthritis
• Tuberculosis
• Leprosy
• Familial Mediterranean Fever
• Paraplegia
• Alzheimer's Disease

Systemic Symptoms
Primary amyloidosis (AL)
The organs that are usually affected in primary amyloidosis (AL) are the heart, kidneys, liver, spleen, skin, lungs, stomach and intestines. Symptoms can include shortness of breath, fatigue, swelling of ankles, dizziness, enlarged tongue, a feeling of fullness, diarrhea, weight loss, numbness in arms and legs and protein in the urine. Primary amyloidosis is a progressive disease that leads to failure of the affected organ and is eventually life threatening.

Secondary amyloidosis (AA)
Symptoms of secondary amyloidosis (AA) include those that are caused by the underlying disease (such as rheumatoid arthritis, familial Mediterranean fever of other chromic infection or inflammatory disease) and typically results in kidney and gastrointestinal dysfunction that can lead to protein in the urine, swelling and fatigue. Secondary amyloidosis is a progressive disease that often leads to end stage kidney disease and is life threatening.

Hereditary amyloidosis
The most common type of hereditary amyloidosis is transthyretin amyloidosis (ATTR). The body tissues most often affected by hereditary amyloidosis are the nerves, heart, kidneys and intestine. Symptoms vary in different families but can include numbness, dizziness and diarrhea. Some affected individuals experience nervous system effects (neuropathy) that begin with a burning pain or lack of sensation in the feet and progress to sensory loss in the hands as well. Some affected individuals develop abnormalities in the electrical function of the heart (cardiac conduction defect) or in the pumping capability of the heart (cardiomyopathy). Approximately 20% of those with a TTR mutation have vision abnormalities in which floaters (vitreous opacities) appear.

Beta2-microglobulin amyloidosis (Aß2M)
Almost invariably this disorder is associated with patients on kidney dialysis and usually affects the bones and joints. Initial symptoms include carpal tunnel syndrome, shoulder pain and inflammation of the tendon sheaths of the hands.

Localized Symptoms
Localized forms of the disease may affect the airways and lung parenchyma, the bladder, skin and eyes.

Amyloidosis can affect the body in many different ways. Symptoms may be present in the following organ systems:

The nephrotic (kidney) syndrome associated with amyloidosis is usually manifested by swellings of the legs and abdomen, and accompanied by increased levels of protein in the urine (proteinuria), which worsens as the disease progresses and may finally result in kidney failure. The kidneys become small, pale and hard. Renal tubular defects, renal vein blood clots (thrombosis) and high blood pressure (hypertension) may also be present. Amyloid may accumulate in other parts of the urogenital system, such as the bladder or urinary tubes (ureter).

Amyloidosis may affect the liver and the spleen. An enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are the most notable signs. Elevated liver enzymes (alkaline phosphatase) and other liver function abnormalities may be detected early. Generally the function of the liver is not significantly affected until late in the course of the disease. Amyloid involvement in the spleen increases the risk of traumatic rupture of that organ.

Amyloidosis frequently involves the heart. Common symptoms of heart involvement include: an enlarged heart (cardiomegaly); an irregular heartbeat (arrhythmias); heart murmurs; and abnormalities of the heart seen on electrocardiograms. Congestive heart failure is the most common cardiac complication of Amyloidosis. Nodular deposits of amyloid may be present on the membranous sac that surrounds the heart (pericardium) and on the lining of the heart chambers or heart valves (endocardial).

Amyloidosis may also affect the gastrointestinal (digestive) system. Amyloid accumulation in the gastrointestinal tract may cause a lack of movement (motility) in the esophagus and the small and large intestines. Malabsorption, ulceration, bleeding, weak gastric activity, pseudo-obstruction of the gastrointestinal tract, protein loss, and diarrhea may also occur. Enlargement of the tongue (macroglossia) may result from amyloid infiltration.

The skin is frequently involved in Amyloidosis. The lesions may be visible or may be so small that they may be seen only with a microscope. Waxy-looking papular lesions may appear on the face and the neck. They may also occur under the arms (axillary region), near the anus and the groin. Other areas that may be affected are the mucous areas such as the ear canal or tongue. Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis) and a dry mouth (xerostomia) may also be present.

Neurological symptoms are a common manifestation of one type of hereditary amyloidosis, as well as in primary amyloidosis (AL). These symptoms may include: sensory neuropathy with numbness and tingling sensations in the feet that progresses to the legs and eventually the upper extremities; motor neuropathy with loss of motion beginning in the feet and extending upward; autonomic neuropathy with symptoms of a decrease in the amount of sweat production (hypohidrosis), a sudden drop in blood pressure when the patient stands up (postural hypotension), and gastrointestinal symptoms including loss of appetite, nausea, diarrhea and constipation.

Problems with the respiratory system that are associated with amyloidosis often parallel cardiac symptoms. In the localized form of amyloidosis air passages and ducts may be obstructed by amyloid deposits in the nasal sinuses, voice box (larynx) and throat (trachea) and bronchial tree.

Joint abnormalities (arthropathy) occur in amyloidosis due to the accumulation of amyloid deposits in the lining of joints (synovial membranes). This occurs in AL amyloidosis and occassionally in the dialysis-related amyloidosis. Articular cartilage or the synovial membrane and fluid may become involved as well. Symptoms are similar to those of rheumatoid arthritis. Amyloid deposits in muscle tissue may cause muscle weakness and muscle changes (pseudomyopathy). Symptoms of amyloidosis may also be manifest by bleeding disorders. These may result from deficiency of certain clotting factors or small amyloid deposits in blood vessels within the skin.
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The cause of primary amyloidosis (AL) is a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody). Usually an excess amount of antibody protein is produced and the abnormal light chain portion or the whole antibody molecule accumulates in the body tissues.

Secondary amyloidosis (AA) is caused by the inflammatory disease process that is part of the underlying disease. Approximately 50% of the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.

Hereditary amyloidosis is caused by an abnormality in the gene for one of several particular proteins. The most common form of hereditary amyloidosis is called ATTR and is caused by an abnormality (mutation) in the gene for transthyretin. Other proteins with mutations that cause amyloidosis are fibrinogen A alpha, lysozyme, apolipoprotein A-I Apolipoprotein A-II, or gelsolin. More than 100 different mutations in the transthyretin gene have been reported and the most common mutation has been termed V30M. Different TTR mutations are associated with amyloidosis that affects different organ systems. All the hereditary amyloidoses follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Approximately 1,200-3,200 new cases of primary amyloidosis (AL) are diagnosed each year in the U.S. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. Primary amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.

Individuals at risk for secondary amyloidosis (AA) include those with chronic inflammatory diseases such as rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis in children, inflammatory bowel disease, and familial Mediterranean fever. People with chronic infectious diseases such as tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis, and chronic pyelonephritis are also at risk. Secondary amyloidosis (AA) occurs in less that 5% of individuals with these conditions.

Hereditary amyloidosis caused by a transthyretin mutation occurs in approximately 1 in 100,000 Caucasians in the U.S. This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 30 and 50 years of age.
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The following disorders may be associated with amyloidosis. Amyloidosis may appear in conjunction with or as a result of the following disorders:

Multiple myeloma, Hodgkin's disease, lymphoma, medullary carcinoma of the thyroid, Whipple's disease, Crohn disease, osteomyelitis, rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, tuberculosis, leprosy, familial Mediterranean fever, paraplegia Alzheimer's disease SK and Waldenstrom’s macroglobulinemia (For more information on these disorders, choose the following as search terms on the Rare Disease Database: "multiple myeloma", "Hodgkin’s, "lymphoma", "Whipple", "Crohn", "osteomyelitis", "ankylosing spondylitis", "Reiter", "arthritis", "tuberculosis", "leprosy", "Mediterranean fever", "paraplegia" , “Waldenstrom’s” and "Alzheimer's".)
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Diagnosis
Early diagnosis is the key to survival and post treatment quality of life.
The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires a biopsy of muscle, bone or fatty tissue to confirm the presence of amyloid. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. The specific tests that are used to make a diagnosis of the AL amyloidosis type are immunofixation electrophoresis of the blood and urine, bone marrow biopsy with immunochemical staining of plasma cells for kappa and lambda light chains and a free light chain assay. Other tests of the immune system and cellular tissue (immunohistochemical analysis) as well as chemical tests are used to determine which type of amyloidosis is present. The diagnosis of ATTR hereditary amyloidosis can be confirmed by performing molecular genetic testing for mutations in the TTR gene on a blood sample. A technique called radiolabeled serum amyloid P (SAP) scanning is available in a few centers in Europe that specialize in amyloidosis. This test is used to monitor the accumulation of amyloid deposits.

When amyloidosis is diagnosed on a tissue biopsy it is essential that the affected individual be further evaluated to determine what organs are affected.

Treatment
Treatment for amyloidosis is supportive and symptomatic and involves a two-part process. The first goal of treatment is to stop or slow the production of the amyloid. If the production is not stopped, the affected organ, tissue or body system will continue to deteriorate. Therefore, a prompt diagnosis and evaluation of organ function should be accomplished as soon as possible.

The second goal of treatment is to restore as much function as possible to the affected body system, organ(s) or tissues. This is typically done with medication, diet, exercise and in some cases organ transplantation or surgery. The greatest risk to an individual with amyloidosis is from a diseased or damaged organ.

For primary amyloidosis, Melphalan has been the treatment of choice. Some affected individuals are eligible for a therapy consisting of high dose Melphalan followed by autologous (patient’s own) stem cell transplantation. Other treatments include drug therapy; oral Melphalan plus Dexamethasone or in various combinations and delivery mechanisms. Newer medications include Velcade and Revlimid.

When amyloidosis is the result of the presence of another disorder, as in secondary (AA) amyloidosis, treatment of the underlying disease sometimes controls the amyloidosis adequately. A positive response to treatment is more likely if treatment begins early in the course of the underlying illness. Cytotoxic drugs such as choloroambucil or cyclophosphamide are used to treat some inflammatory disorders. Colchicine therapy is frequently used to treat those affected with amyloidosis as a result of familial Mediterranean fever. A new drug, Fibrillex, has completed testing in clinical trial and found useful for AA amyloidosis. It works as a targeted inhibitor to prohibit the precursor amyloid protein from depositing in tissues. It is awaiting FDA approval.

In cases with severe kidney (renal) involvement or in cases caused by long-term renal dialysis kidney transplantation may be necessary. Kidney transplantation is most successful when the disease process has been stopped, otherwise there is some risk that amyloidosis will recurs in the transplanted kidney.

Heart transplantation may be an option in amyloidosis when only the heart is severely affected. This happens rarely in AL amyloidosis. After transplantation the patient must be treated for the bone marrow disorder.

Currently the only effective therapy for certain forms of hereditary (ATTR) amyloidosis is liver transplantation. Individuals may be eligible for this treatment if they have a form of ATTR amyloidosis that affects the nervous system. An international multicenter clinical trial is underway to test Diflunisal, a drug that may inhibit amyloid fibril formation in mutant TTR amyloidosis. Genetic counseling may be of benefit for individuals with hereditary amyloidosis and their family members.

Localized amyloid tumors may be surgically removed or simply observed. While they usually cannot be completely removed, they tend to reaccumulate very slowly.

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Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Amyloidosis treatment centers are located at Boston University, the Mayo Clinic and Memorial Sloan-Kettering Cancer Center. These centers have established practices that also conduct research and clinical trials.

Patients with familial amyloidosis are being recruited for a study sponsored by FoldRx Pharmaceuticals, Inc., of its investigational drug Fx-1006A. Specifically, the company is looking for patients with familial amyloid polyneuropathy (FAP) who have a certain genetic mutation known as V30M TTR. TTR is a hormone-carrying protein that circulates in the blood. In patients with this mutation, TTR becomes destabilized and misfolds, resulting in amyloid deposits in various tissues. The study is investigating the possible use of Fx-1006A to stabilize TTR and, therefore, stop the progression of the disease. The drug has orphan designation in the U.S. and the European Union. In the U.S., it has "fast-track" designation for the treatment of FAP.

The U.S. Food and Drug Administration (FDA) has designated the orphan drug Fibrillex a Fast Track Product (FTP) for the treatment of secondary (AA) amyloidosis (February 2004). Fibrillex is an oral product designed to slow or stop progression of the disease. Information on Fibrillex is available from:

Neurochem, Inc.
722 Frederick-Bantin St.
Suite 100
Saint-Laurent, Quebec
Canada H4S2A1
Telephone: (514) 337-4646
Website: www.neurochem.com

Information on clinical trials related to amyloidosis is available from the following resources:

Boston University School of Medicine
Ms. Wendy Trafton or Dr. Martha Skinner
Amyloid Treatment and Research Program
715 Albany Street K5
Boston, MA 02118
Tel: (617) 638-4317
Fax: (617) 638-4493
E-mail: buamyloid@amyloid.bu.edu
http://amyloid.bu.edu/amyloid

Mayo Clinic
Morie A. Gertz, M.D.
Dept. of Hematology and Internal Medicine
Rochester, MN 55905
(507) 284-2511

Memorial Sloan Kettering Cancer Center
Raymond L. Comenzo, M.D.
1275 York Avenue
New York, NY 10021
212) 639-8086

University of Tennessee Graduate School of Medicine
Alan Solomon, MD
1924 Alcoa Highway
Knoxville, TN 37920
Tel:(865) 544-9165
Fax:(865) 544-6865
e-mail: asolomon@mc.utmck.edu

Indiana University School of Medicine
Merrill Benson, M.D.
1481 West 10th Street
Indianapolis, IN 56201
(317) 278-3426

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REVIEW ARTICLES
Amyloidosis - Morie A. Gertz* MD, Martha Q. Lacy MD, Angela Dispenzieri MD, Suzanne R. Hayman MD Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Best Practice & Research Clinical Haematology Vol. 18, No. 4, pp. 709–727, 2005 This paper reviews a diagnostic pathway clinicians can use to diagnose the disorder, assess a patient’s prognosis, and logically plan a therapeutic strategy.

Park KI, Ourednik J, Ourednik V, et al. Global gene and cell replacement strategies via stem cells. Gene Ther. 2002;9:613-24.

Rocken C, Shakespeare A. Pathology, diagnosis and pathogenesis of AA amyloidosis. Virchows Arch. 2002;440:111-22.

Greenberg SM. Cerebral amyloid angiopathy and vessel dysfunction. Cerebrovasc Dis. 2002;13 Suppl 2:42-47.

Gertz MA, Lacy MQ, Dispenzieri A. Immunoglobulin light chain amyloidosis and the kidney. Kidney Int. 2002;61:1-9.

Jaikaran ET, Clark A. Islet amyloid and type 2 diabetes; from molecular misfolding to islet pathophysiology. Biochim Biophys Acta. 2001;1537:179-203.

Sanchorawala V, Wright DG, Seldin DC, et al. An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant. 2001;28:637-42.
Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O’Hara CJ, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Annals Int Med, 140: 85-93, 2004.
Seldin DC, Anderson JJ, Sanchorawala V, Malek K, Wright DG, Quillen K, Finn KT, Berk JL, Dember LM, Falk RH, Skinner M: Improvement in quality of life of patients with AL amyloidosis treated with high dose melphalan and autologous stem cell transplantation. Blood, 104: 1888-1893, 2004.

Khan MF, Falk RH. Amyloidosis. Postgrad Med J. 2001;77:686-93.

Dobson CM. Protein folding and its links to human disease. Biochem Soc Sympos. 2001;68:1-26.

Adams D. hereditary and acquired amyloid neuropathies. J Neurol. 2001;248:647-57.

Saraiva MJ. Transthyretin amyloidosis: a tale of weak interactions. FEBS Lett. 2001;498:201-03.

Floege J, Schaffer J, Koch KM. Scintigraphic methods to detect beta2-microglobulin associated amyloidosis (Abeta2-microglobulin amyloidosis). Nephrol Dial Transplant. 2001;16 Suppl 4:12-16.

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Cunnane G. Amyloid precursors and amyloidosis in inflammatory arthritis. Curr Opin Rheumatol. 2001;13:67-73.

Plante-Bordeneuve V, Said G. Transthyretin related familiar amyloid polyneuropathy. Curr Opin Neurol. 2000;13:569-73.

Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis - Morie A. Gertz,* Ray Comenzo, Rodney H. Falk, Jean Paul Fermand, Bouke P. Hazenberg, Philip N. Hawkins, Giampaolo Merlini, Philippe Moreau, Pierre Ronco, Vaishali Sanchorawala, Orhan Sezer, Alan Solomon, and Giles Grateau - Am. J. Hematol. 79:319–328, 2005. This paper presents criteria that centers can now use to define organ involvement and uniform response criteria for reporting outcomes in patients with AL.

GUIDELINES ON THE DIAGNOSIS AND MANAGEMENT OF AL AMYLOIDOSIS - By the British Committee for Standards in Hematology 2004 in conjunction with Working Group of the UK Myeloma Forum (UKMF). Updates may be found at http://www.ukmf.org.uk and http://www.bcshguidelines.com


FROM THE INTERNET
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Mellors RC. Weill Medical College of Cornell University. Amyloidosis. 1999:9pp.
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