Amyloidosis

Amyloidosis is a group of diseases in which amyloid—a protein-like substance—builds up in the organs and tissues. The buildup may happen systemically (throughout the body) or locally (in one tissue).

There are four major types of systemic amyloidosis:

• Primary amyloidosis (the most common form), typically caused by a buildup of fragments of antibody proteins
• Hereditary amyloidosis, a genetic form passed down in families
• Reactive or secondary amyloidosis, which develops along with a chronic inflammatory disease, such as rheumatoid arthritis
• Beta2-microglobulin amyloidosis—beta2-microglobulin is a protein that can build up in the blood as a result of kidney failure. This type of amyloidosis occurs in people who have been on dialysis for a long time.

Amyloid deposits can affect any organ or tissue. Localized amyloidosis affects more than 90% of people with Type II diabetes mellitus, people with certain cancers of the thyroid or other tumors of the endocrine system, and about 80% of people over age 80. It also affects people with conditions such as Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage, and the disease commonly known as "mad cow disease."

Signs and Symptoms

The signs and symptoms depend on the location and size of the amyloid deposits.

Any tissue may be affected in primary amyloidosis. Signs and symptoms may include the following:

• Heart disease and irregular heart beat
• Kidney disorders, including kidney failure
• Gastrointestinal (GI) disorders, such as perforation (hole), bleeding, slow movement of matter through the GI tract, and blockage
• Enlarged liver
• Diminished function of the spleen
• Diminished function of the adrenal and other endocrine glands
• Problems in transmitting nerve signals, which could lead to impotence, gastrointestinal problems, and orthostatic hypotension (low blood pressure upon standing)
• Carpal tunnel syndrome (compression and irritation of the median nerve in the wrist)
• Skin conditions, such as growths, color changes, purpura (bleeding into the skin) around the eyes, and easy bruising
• Enlarged tongue, sometimes with swelling under the jaw, breathing difficulties, and sleep apnea
• Lung problems
• Swelling of the shoulder joints (may look like shoulder pads under the skin)
• Susceptibility to bleeding problems

Signs and symptoms of hereditary amyloidosis may include the following:

• Nervous system disorders
• Gastrointestinal conditions, such as diarrhea and weight loss
• Heart problems
• Kidney disease, though this is less common than in primary amyloidosis

Signs and symptoms of secondary amyloidosis may include the following:

• Kidney disease, which may lead to kidney failure; this is the cause of death in 40 to 60% of cases
• Enlarged liver
• Enlarged spleen
• Heart problems—this is rare, and less severe than in other forms of amyloidosis

Most people who are diagnosed with secondary amyloidosis have had their related inflammatory disease for a decade or more.

Beta2-microglobulin amyloidosis usually occurs in people who have end-stage renal (kidney) disease and need long-term dialysis, but it also can occur in people who use ambulatory dialysis. Deposits are often found in bones and joints. Such deposits may cause carpal tunnel syndrome, joint pain and stiffness, soft tissue masses, bone cysts, and fractures.

What Causes It?

The body naturally makes amyloid as it ages and deposits the amyloid in the space surrounding the cells. Some people accumulate abnormal amounts of amyloid, causing amyloidosis. Many factors can play a part in this; the process depends on the form of the disease. Hereditary amyloidosis results from genetic changes that cause the body to make abnormal proteins. Age seems to play a role in amyloidosis—researchers think the disease may be triggered by damage that accumulates in the body over time. This kind of damage may come from the body's use of oxygen (oxidation) and from free radicals (harmful by-products formed when cells use energy). Amyloid is also more likely to form in people who have immune system problems. Once amyloid deposits have started, they seem to continue building up in the same locations.

Who's Most At Risk?

People with the following profile are at increased risk for developing amyloidosis:

• Men
• Being more than 50 years old. Cases do occur in younger adults and children, usually in those with an inflammatory condition such as juvenile rheumatoid arthritis. However, most cases are diagnosed in older people. Even in people with hereditary forms, amyloid deposits severe enough to cause problems are detected later in life.
• Disease affecting the antibody-producing plasma cells in the blood (such as multiple myeloma, malignant lymphoma, benign monoclonal gammopathy, or Waldenström's macroglobulinemia)
• Chronic inflammatory disease (such as rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, or ankylosing spondylitis); this may cause secondary amyloidosis
• Long-term dialysis—almost all patients with end-stage renal disease who are on hemodialysis for more than 5 years develop amyloid deposits
• Inherited genetic changes that affect proteins in the body
• Long-term infection such as leprosy, tuberculosis, or osteomyelitis; this may bring on secondary amyloidosis

What to Expect at Your Provider's Office

Your healthcare provider may suspect amyloidosis based on your symptoms. Tests of blood, urine, bone marrow, or biopsies (samples of tissue) from abdominal fat, the rectum, or an affected organ may show signs of amyloid deposits. With hereditary amyloidosis, DNA tests may reveal the genetic change that caused the condition. Specialized X-ray studies of tissue samples may show the structure of amyloid deposits. Depending on the signs and symptoms, your healthcare provider may use other tests to find out more about your condition, such as which organs are affected and whether your condition is getting worse.

Treatment Options

Prevention
Those who have hereditary amyloidosis in their family should consider going to genetic counseling to learn about the risks of passing the condition to their children.

Treatment Plan
In most people, treatment can help support health and reduce the impact of amyloidosis, but cannot cure the disease. Treatment involves decreasing the proteins that can make up amyloid. Chemotherapy is used for primary amyloidosis. There is no treatment per se for secondary amyloidosis; the underlying condition must be treated. A liver transplant may be necessary for hereditary amyloidosis. A kidney transplant may cure amyloidosis related to dialysis.

Drug Therapies
Under select circumstances, certain drug combinations, many of which are under investigation, have been used to treat primary amyloidosis. For amyloidosis related to kidney failure, researchers are studying other treatments, such as using new dialysis systems and adding antioxidants to the dialysis fluid; antioxidants may help rid the body of unstable compounds known as free radicals.

To help relieve symptoms, a healthcare provider may suggest:

• Diuretics to relieve swelling caused by fluid retention
• Anti-arrhythmics to control heart rhythm
• Metoclopramide to help empty food from the stomach
• Antibiotics to control bacteria that may cause diarrhea or prevent the body from absorbing nutrients

Surgical and Other Procedures

Depending on which parts of the body are affected, the person with amyloidosis may need one of the following procedures:

• Dialysis for those whose kidneys are failing
• Kidney, liver, heart, or bone marrow transplant
• Spleen removal
• Carpal tunnel surgery
• Hip replacement
• Pacemaker implantation to control heart rhythm

Complementary and Alternative Therapies

Dietary choices, supplements, and herbs that aid in diminishing inflammation in general may, theoretically, help to prevent amyloidosis. Damage from oxidation may play a role in development of amyloidosis (see section entitled What Causes It?), particularly beta2-microglobulin, the form of amyloidosis related to hemodialysis. Along with changing dialysis methods, adding antioxidants may slow the disease. Animal studies support the idea that dietary changes to decrease inflammation and provide antioxidants slow the development of amyloidosis. Nutrition Several studies have examined the role of diet in amyloidosis. Some animal studies suggest that the following dietary choices may help prevent the disease for one who is at high risk or slow the disease process once amyloidosis has developed:

• Limit the amount of meat consumed; researchers suspect that a substance called amyloid enhancing factor (AEF), sometimes found in diseased animal foods, may increase the risk of amyloidosis in people who eat these foods; AEF does hasten the growth of amyloid deposits in mice.
• Take fish oil supplements, which are high in omega-3 fatty acids; helps to reduce inflammation in chronic inflammatory conditions such as rheumatoid arthritis and appears to help prevent amyloidosis in mice.
• Vitamin C – a well designed animal study suggested that high doses of vitamin C may help the body break down amyloid and prevent amyloidosis from worsening.

While of these results represent a beginning and show promise, it is difficult to draw definitive conclusions about people from animal findings.

Additional nutritional information includes:

• Bromelain, an enzyme derived from pineapple, may help break down amyloid deposits in kidney tissue; this is suggested by a laboratory study performed on tissue samples from the kidney of one person with a family history of amyloidosis; this preliminary finding does not indicate how this information will translate to treatment or prevention of amyloidosis for people in general.
• Glutathione – low levels may be associated with higher levels of beta2-microglobulin in people on dialysis with or without amyloidosis; this suggests that there may be a link between glutathione levels in the blood and development or worsening of beta2-microglobulin amyloidosis. Although studies have not been conducted to evaluate supplementation with glutathione for amyloidosis, some clinicians may recommend 500 mg two or three times a day to people on dialysis to try to prevent the disease.

Traditionally, certain health care professionals have recommended the following to try to help prevent inflammation in general:

• Avoid processed foods, caffeine, food additives, dairy products, and refined sugars.
• Eat more whole grains, fresh fruits and vegetables, nuts, seeds, and cold-water fish.

Herbs
Flavonoids are plant compounds that fight damage from oxidation and free radicals, as well as inflammation. They may be useful as a complement to standard medical care in treating amyloidosis:

• Pycnogenol, which comes from the bark of French maritime pine (Pinus maritima), is rich in flavonoids. One laboratory study suggested that pycnogenol protected cells of cattle from free radical damage due to amyloid deposits.
• Gingko biloba extract (GBE) also contains flavonoids. GBE has shown good results compared to standard medications for treating Alzheimer's disease. Given the link between Alzheimer's and amyloid deposits, GBE may help treat amyloidosis as well, especially because it is also an antioxidant.

Prognosis/Possible Complications

Most people with primary amyloidosis die within two years of diagnosis, usually of heart failure, uremia (toxic buildup of wastes in the blood), or other complications. About 20% survive 5 years or longer. With secondary amyloidosis, most people survive 5 to 10 years after their condition surfaces. Survival depends on how well the underlying condition is treated. In hereditary amyloidosis, the outlook varies depending on the type of gene mutation and when the condition is diagnosed. Some people survive as long as 15 years after the disease develops. In people with certain mutations that cause problems earlier in life (around age 20 to 30), the disease tends to worsen more quickly and cause death sooner. Kidney transplants stop beta2-microglobulin amyloidosis, but most patients are poor candidates for surgery.

People with amyloidosis affecting the heart are extremely sensitive to certain medicines. Digoxin may cause fatal irregular heartbeat. Calcium-channel blockers may worsen congestive heart failure. Diuretics and vasodilators may cause life-threatening low blood pressure.

Following Up

After diagnosis, tests may be performed on a regular basis to check levels of protein-related substances, the size and placement of amyloid deposits, the development of the disease, and the effects of treatment.

References

Adachi N, Koh CS, Tsukada N, Shoji S, Yanagisawa N. In vitro degradation of amyloid material by four proteases in tissue of a patient with familial amyloidotic polyneuropathy. J Neurol Sci. 1988;84(2-3):295-299.

Akpolat I, Akpolat T, Danaci M, Baris YS, Kaya N, Kandemir B. Behcet's disease and amyloidosis. Review of the literature. Scand J Rheumatol. 1997;26(6):477-479.

Amyloidosis. MedlinePlus. Accessed at https://medlineplus.gov/ on January 23, 2018.

Antibiotics. NMIHI. Accessed at http://drugs.nmihi.com/antibiotics.htm on January 23, 2018.

Ampicillin. NMIHI. Accessed at http://www.nmihi.com/a/ampicillin.html on January 23, 2018.

Amyloidosis. Symptoms and causes. MFMER. Accessed at https://www.mayoclinic.org/ on January 23, 2018.

Baltz ML, Caspi D, Glatthaar BE, Moser U, Pepys MB. The failure of ascorbic acid therapy to alter the induction or remission of murine amyloidosis. Clin Exp Immunol. 1984;57(3):657-662.

Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R. The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci. 2000;12(6):1882-1890.

Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:218-220.

Bellotti V, Merlini G. Current concepts on the pathogenesis of systemic amyloidosis. Nephrol Dial Transplant. 1996;11(suppl 9):53-62.

Benson MD. Inherited amyloidosis. J Med Genet. 1991;28(2):73-78.

Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1997:1427-1429.

Buxbaum J. The amyloidoses. Mt Sinai J Med. 1996;63(1):16-23.

Cathcart ES, Elliott-Bryant R. Diet, amyloid enhancing factor (AEF) and amyloidogenesis: an hypothesis. Amyloid. 1999;6(2):107-113.

Cathcart ES, Leslie CA, Meydani SN, Hayes KC. A fish oil diet retards experimental amyloidosis, modulates lymphocyte function, and decreases macrophage arachidonate metabolism in mice. J Immunol. 1987;139(6):1850-1854.

Co-amoxiclav. NMIHI. Accessed at http://www.nmihi.com/c/co-amoxiclav.html on January 23, 2018.

Cohen AS. Clinical aspects of amyloidosis, including related proteins and central nervous system amyloid. Curr Opin Rheumatol. 1994;6(1):68-77.

Cohen AS. Primary (AL) amyloidosis. Ren Fail. 1993;15(3):429-433.

David J, Woo P. Reactive amyloidosis. Arch Dis Child. 1992;67(3):258-261.

Diuretics. NMIHI. Accessed at http://drugs.nmihi.com/diuretics.htm on January 23, 2018.

Elliott-Bryant R, Cathcart ES. Amyloid enhancing factor and dietary transmission in accelerated amyloid A amyloidosis. Clin Immunol Immunopathol. 1998;88(1):65-69.

Falk RH, Comenzo RL, Skinner M. Medical progress: the systemic amyloidoses. N Engl J Med. 1997;337(13):898-909.

Falk RH, Skinner M. The systemic amyloidoses: an overview. Adv Intern Med. 2000;45:107-137.

Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. Vol 2. 14th ed. New York, NY: McGraw-Hill; 1998:1856-1859.

Frank MM, Austen KF, Claman HN, Unanue ER, eds. Samter's Immunologic Disease. Vol 1. 5th ed. Boston, Mass: Little, Brown and Co; 1995:637-653.

Friedman S, Janowitz HD. Systemic amyloidosis and the gastrointestinal tract. Gastroenterol Clin North Am. 1998;27(3):595-614.

Friman C, Pettersson T. Amyloidosis. Curr Opin Rheumatol. 1996;8(1):62-71.

Furosemide. NMIHI. Accessed at http://www.nmihi.com/f/furosemide.html on January 23, 2018.

Gertz MA, Kyle RA. Phase II trial of alpha-tocopherol (vitamin E) in the treatment of primary systemic amyloidosis. Am J Hematol. 1990;34(1):55-58.

Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis. Hematol Oncol Clin North Am. 1999;13(6):1211-1233.

Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments. Br J Haematol. 1997;99(2):245-256.

Gillmore JD, Hawkins PN. Amyloidosis and the respiratory tract. Thorax. 1999;54(5):444-451.

Harman D. Nutritional implications of the free-radical theory of aging. J Am Coll Nutr. 1982;1(1):27-34.

Hawkins PN. The diagnosis, natural history, and treatment of amyloidosis. The Goulstonian Lecture 1995. J R Coll Physicians Lond. 1997;31(5):552-560.

Husby G. Classification of amyloidosis. Baillieres Clin Rheumatol. 1994;8(3):503-511.

Isobe T. AA amyloidosis and AL amyloidosis. Intern Med. 1993;32(12):919-920.

Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Adv Hum Genet. 1991;20:69-123, 309-311.

Koopman WJ. Arthritis and Allied Conditions: A Textbook of Rheumatology. 13th ed. Baltimore, Md: Williams & Wilkins; 1997:1661-1684.

Lebrazi H, Hachulla E, Saile R. Treatments for amyloidosis beyond symptomatic care [in French]. Rev Med Interne. 2000;21(3):247-255.

Lins RL, Zachee P, Daelemans R, Vanden Broecke E, Boogaerts MA, De Broe ME. Red blood cell function and beta 2 microglobulin kinetics during cuprophan hemodialysis: a hypothesis. Int J Artif Organs. 1989;12(10):638-641.

Liu F, Lau BH, Peng Q, Shah V. Pycnogenol protects vascular endothelial cells from beta-amyloid-induced injury. Biol Pharm Bull. 2000;23(6):735-737.

Miyata T, Inagi R, Kurokawa K. Diagnosis, pathogenesis, and treatment of dialysis-related amyloidosis. Miner Electrolyte Metab. 1999;25(1-2):114-117.

Morena M, Cristol J, Canaud B. Why hemodialysis patients are in a prooxidant state? What could be done to correct the pro/antioxidant imbalance. Blood Purif. 2000;18(3):191-199.

Pascali E. Diagnosis and treatment of primary amyloidosis. Crit Rev Oncol Hematol. 1995;19(3):149-181.

Ravid M, Chen B, Bernheim J, Kedar I. Ascorbic acid-induced regression of amyloidosis in experimental animals. Br J Exp Pathol. 1985;66(2):137-141.

Rosen P, et al. Emergency Medicine: Clinical Concepts and Clinical Practice. Vol 2. 4th ed. St. Louis, Mo: Mosby; 1998:1738.

Sezer O, Eucker J, Schmid P, Possinger K. New therapeutic approaches in primary systemic AL amyloidosis. Ann Hematol. 2000;79(1):1-6.

Simms RW, Prout MN, Cohen AS. The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol. 1994;8(3):627-634.

Sipe JD. Amyloidosis. Crit Rev Clin Lab Sci. 1994;31(4):325-354.

Tan SY, Pepys MB, Hawkins PN. Treatment of amyloidosis. Am J Kidney Dis. 1995; 26(2):267-285.

Tan SY, Pepys MB. Amyloidosis. Histopathology. 1994;25(5):403-414.

Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol. 1988;22(2):191-203.

Thoene JG, et al. Physicians' Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Co; 1995:749-750.

Tinaztepe K. Renal amyloidosis in childhood. An overview of the topic with 25 years experience. Turk J Pediatr. 1995;37(4):357-373.

Vogelgesang SA, Klipple GL. The many guises of amyloidosis. Clinical presentations and disease associations. Postgrad Med. 1994;96(5):119-122, 126-127.

Wettstein A. Cholinesterase inhibitors and ginkgo extracts—are they comparable in the treatment of dementia? Phytomedicine. 2000;6(6):393-401.

Woo P. Amyloidosis in children. Baillieres Clin Rheumatol. 1994;8(3):691-697.

What is amyloidosis? NIH. Accessed at https://www.niddk.nih.gov/ on January 23, 2018.