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Hereditary amyloidosis

Amyloid describes various types of protein aggregations that share specific traits when examined microscopically. The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, rather a deposition of proteinaceous mass. more...

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Specifically, amyloid deposits are extracellular, thioflavin s positive, and exhibit apple-green birefringence when stained with congo red. Other indicators exist, such as serum amyloid p-component binding. Since these are indirect indicators, biophysicists have redefined amyloid using a canonical set of biophysical characteristics (see below), and this seems to cause a low level of conflict between histologists and biophysicists.

The phenotypes of genetically transmitted amyloid diseases are often inherited in an autosomal dominant fashion. Sometimes, the difference between aggressive amyloid diseases and senescent amyloid diseases is due to a mutation which makes the protein more prone to aggregation. Most commonly seen are point mutations which affect the cohesiveness of the protein and promote misfolding; other mutations cause aggregation-prone pieces of the protein to be cleaved off from the rest of the protein.

Diseases featuring amyloid

It should be noted that in almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or if they are instead a symptom downstream of a common ideopathic agent. The associated proteins are indicated in parentheses.

  • Systemic amyloidosis
    • Primary amyloidosis
      • Mutations in lysozyme, transthyretin, apolipoprotein B, fibrinogen
    • Secondary amyloidosis
      • AA amyloidosis (amyloid A protein, an acute phase protein due to chronic inflammation)
      • AL amyloidosis (immunoglobulin light chains)
      • Gelsolin amyloidosis (plasma gelsolin fragments).
    • Familial or Hereditary amyloidosis
      • Most commonly caused by mutations in the transthyretin protein, but in rare occurrences can also be caused by apolipoprotein A1, gelsolin, fibrinogen, and lysozyme mutations.
      • Primarily caused by genetics, believed to be autosomal dominant, high probability of passage to offspring
      • Appalachian type amyloidosis is perhaps the most well known type
  • Organ-specific amyloidosis
    • Diabetes mellitus type 2 (amylin, also known as IAPP)
    • Neurology
      • Alzheimer's disease (Aβ 39-42)
      • Parkinson's disease (alpha-synuclein) -- biophysical definition
      • Huntington's disease (huntingtin) -- biophysical definition
      • Spongiform encephalopathies
        • Creutzfeldt-Jakob disease (PrP in cerebrum)
        • Kuru (diffuse PrP deposits in brain)
        • Fatal Familial Insomnia (PrP in thalamus)
        • Bovine spongiform encephalopathy (PrP in cerebrum)
      • Congophilic angiopathy (Amyloid beta)
      • congestive heart failure; some instances (PrP in heart)
    • Inclusion body myositis
  • Iatrogenic conditions
    • insulin amyloidosis (injection-administered insulin)

Read more at Wikipedia.org


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Amyloidosis
From Gale Encyclopedia of Medicine, 4/6/01 by Maureen Haggerty

Definition

Amyloidosis is a progressive, incurable, metabolic disease characterized by abnormal deposits of protein in one or more organs or body systems.

Description

Amyloid proteins are manufactured by malfunctioning bone marrow. Amyloidosis, which occurs when accumulated amyloid deposits impair normal body function, can cause organ failure or death. It is a rare disease, occurring in about eight of every 1,000,000 people. It affects males and females equally and usually develops after the age of 40. At least 15 types of amyloidosis have been identified. Each one is associated with deposits of a different kind of protein.

Types of amyloidosis

The major forms of this disease are primary systemic, secondary, and familial or hereditary amyloidosis. There is also another form of amyloidosis associated with Alzheimer's disease.

Primary systemic amyloidosis usually develops between the ages of 50 and 60. With about 2,000 new cases diagnosed annually, primary systemic amyloidosis is the most common form of this disease in the United States. Also known as light-chain-related amyloidosis, it may also occur in association with multiple myeloma (bone marrow cancer).

Secondary amyloidosis is a result of chronic infection or inflammatory disease. It is often associated with:

  • Familial Mediterranean fever (a bacterial infection characterized by chills, weakness, headache, and recurring fever)
  • Granulomatous ileitis (inflammation of the small intestine)
  • Hodgkin's disease (cancer of the lymphatic system)
  • Leprosy
  • Osteomyelitits (bacterial infection of bone and bone marrow)
  • Rheumatoid arthritis.

Familial or hereditary amyloidosis is the only inherited form of the disease. It occurs in members of most ethnic groups, and each family has a distinctive pattern of symptoms and organ involvement. Hereditary amyloidosis is though to be autosomal dominant, which means that only one copy of the defective gene is necessary to cause the disease. A child of a parent with familial amyloidosis has a 50-50 chance of developing the disease.

Amyloidosis can involve any organ or system in the body. The heart, kidneys, gastrointestinal system, and nervous system are affected most often. Other common sites of amyloid accumulation include the brain, joints, liver, spleen, pancreas, respiratory system, and skin.

Causes & symptoms

The cause of amyloidosis is unknown. Most patients have gastrointestinal abnormalities, but other symptoms vary according to the organ(s) or system(s) affected by the disease. Usually the affected organs are rubbery, firm, and enlarged.

Heart

Because amyloid protein deposits can limit the heart's ability to fill with blood between beats, even the slightest exertion can cause shortness of breath. If the heart's electrical system is affected, the heart's rhythm may become erratic. The heart may also be enlarged and heart murmurs may be present. Congestive heart failure may result.

Kidneys

The feet, ankles, and calves swell when amyloidosis damages the kidneys. The kidneys become small and hard, and kidney failure may result. It is not unusual for a patient to lose 20-25 pounds and develop a distaste for meat, eggs, and other protein-rich foods. Cholesterol elevations that don't respond to medication and protein in the urine (proteinuria) are common.

Nervous system

Nervous system symptoms often appear in patients with familial amyloidosis. Inflammation and degeneration of the peripheral nerves (peripheral neuropathy) may be present. One of four patients with amyloidosis has carpal tunnel syndrome, a painful disorder that causes numbness or tingling in response to pressure on nerves around the wrist. Amyloidosis that affects nerves to the feet can cause burning or numbness in the toes and soles and eventually weaken the legs. If nerves controlling bowel function are involved, bouts of diarrhea alternate with periods of constipation. If the disease affects nerves that regulate blood pressure, patients may feel dizzy or faint when they stand up suddenly.

Liver and spleen

The most common symptoms are enlargement of these organs. Liver function is not usually affected until quite late in the course of the disease. Protein accumulation in the spleen can increase the risk of rupture of this organ due to trauma.

Gastrointestinal system

The tongue may be inflammed, enlarged, and stiff. Intestinal movement (motility) may be reduced. Absorption of food and other nutrients may be impaired (and may lead to malnutrition), and there may also be bleeding, abdominal pain, constipation, and diarrhea.

Skin

Skin symptoms occur in about half of all cases of primary and secondary amyloidosis and in all cases where there is inflammation or degeneration of the peripheral nerves. Waxy-looking raised bumps (papules) may appear on the face and neck, in the groin, armpits, or anal area, and on the tongue or in the ear canals. Swelling, hemorrhage beneath the skin (purpura), hair loss, and dry mouth may also occur.

Respiratory system

Airways may be obstructed by amyloid deposits in the nasal sinus, larynx and traches (windpipe).

Diagnosis

Blood and urine tests can reveal the presence of amyloid protein, but tissue or bone-marrow biopsy is necessary to positively diagnose amyloidosis. Once the diagnosis has been confirmed, additional laboratory tests and imaging procedures are performed to determine:

  • Which type of amyloid protein is involved
  • Which organ(s) or system(s) have been affected
  • How far the disease has progressed.

Treatment

The goal of treatment is to slow down or stop production of amyloid protein, eliminate existing amyloid deposits, alleviate underlying disorders (that give rise to secondary amyloidosis), and relieve symptoms caused by heart or kidney damage. Specialists in cardiology, hematology (the study of blood and the tissues that form it), nephrology (the study of kidney function and abnormalities), neurology (the study of the nervous system), and rheumatology (the study of disorders characterized by inflammation or degeneration of connective tissue) work together to assess a patient's medical status and evaluate the effects of amyloidosis on every part of the body.

Colchicine (Colebenemid, Probeneaid), prednisone, (Prodium), and other anti-inflammatory drugs can slow or stop disease progression. Bone-marrow and stem-cell transplants can enable patients to tolerate higher and more effective doses of melphalan (Alkeran) and other chemotherapy drugs prescribed to combat this non-malignant disease. Surgery can relieve nerve pressure and may be performed to correct other symptom-producing conditions. Localized amyloid deposits can also be removed surgically. Dialysis or kidney transplantation can lengthen and improve the quality of life for patients whose amyloidosis results in kidney failure. Heart transplants are rarely performed.

Supportive measures

Although no link has been established between diet and development of amyloid proteins, a patient whose heart or kidneys have been affected by the disease may be advised to use a diuretic or follow a low-salt diet.

Prognosis

Most cases of amyloidosis are diagnosed after the disease has reached an advanced stage. The course of each patient's illness is unique but death, usually a result of heart disease or kidney failure, generally occurs within a few years. Amyloidosis associated by multiple myeloma usually has a poor prognosis. Most patients with both diseases die within one to two years.

Prevention

Genetic counseling may be helpful for patients with hereditary amyloidosis and their families. Use of cholchicine in patients with familial Mediterranean fever has successfully prevented amyloidosis.

Key Terms

Amyloid
A waxy, starch-like protein.
Peripheral nerves
Nerves that carry information to and from the spinal cord.
Stem cells
Parent cells from which other cells are made.

Further Reading

For Your Information

    Books

  • Fauci, Anthony S., et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw Hill, 1998.

    Organizations

  • Amyloidosis Network International. 7118 Cole Creek Drive, Houston, TX 77092-1421. (713) 466-4351. (888) 1AMYLOID.
  • National Organization for Rare Disorders. P.O. Box 8923, New Fairfield, CT 06812-8923. (800) 999-6673. http://www.nord.rab.com/~orphan

    Other

  • Information for Patients About Primary Amyloidosis. http://www.mayo.edu/mmgrglist/aapamph.htm (8 May 1998).
  • An Informational Guide for Patients with Amyloidosis. http://www.medicine.bu.edu/amyloid/amyloid1.htm (9 May 1998).

Gale Encyclopedia of Medicine. Gale Research, 1999.

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