Amyloidosis

Amyloidosis develops as a result of abnormal protein deposits in various organs and tissues.

Amyloidosis is a group of diseases that are a consequence of abnormal protein deposits in various tissues of the body. These abnormal proteins are called amyloid. Depending on the structure of the particular amyloid, the protein can accumulate in an isolated tissue or be widespread, affecting numerous organs and tissues. There are over 30 different amyloid proteins. Each amyloid protein is arranged in a structure called a fibril. Fibrils are low molecular weight proteins that are derived from precursor proteins. Fibrils of amyloid can float in the plasma of blood and deposit into tissues of the body.

Amyloid protein can be deposited in a localized area and may not be harmful or only affect a single tissue of the body impairing its function. This form of amyloidosis is called localized amyloidosis. Amyloidosis that affects many tissues throughout the body is referred to as systemic amyloidosis. The systemic form can cause serious changes in virtually any organ of the body, including the kidneys (renal amyloidosis), heart (cardiac amyloidosis), skin (cutaneous amyloidosis), and lungs (pulmonary amyloidosis).

Systemic amyloidosis has been classified into three major types that are very different from each other. These are distinguished by a two-letter code that begins with an A (for amyloid). The second letter of the code stands for the protein that accumulates in the tissues in that particular type of amyloidosis. The major types of systemic amyloidosis are currently categorized as primary (now AL), secondary (AA), and hereditary (ATTR, amyloid apolipoprotein A1 or AApoAI, amyloid apolipoprotein A2 or AApoAII, AGel, ALys, AFib).

Amyloidosis that occurs as its own entity has been called primary amyloidosis. It is currently referred to as AL amyloidosis to signify that immunoglobulin light-chain proteins are produced as a result. Secondary amyloidosis is amyloidosis that occurs as a byproduct of another illness, including chronic infections (such as tuberculosis or osteomyelitis), or chronic inflammatory diseases (such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease). Other forms of amyloidosis include beta-2 microglobulin amyloidosis from chronic kidney dialysis and localized amyloidosies. Amyloidosis that is localized to a specific body area from aging does not have systemic implications for the rest of the body. The protein that deposits in the brain of patients with Alzheimer's disease is a form of amyloid.

Immunoglobulin light chain (AL) amyloidosis (formerly referred to as primary amyloidosis)

Immunoglobulin light chain or AL amyloidosis (formerly primary amyloidosis), occurs when a specialized cell in the bone marrow (plasma cell) spontaneously overproduces a particular protein portion of an antibody called the light chain. (This is why the primary form is now referred to as AL.) The deposits in the tissues of people with primary amyloidosis are AL proteins. It can affect the heart, kidney, liver, and skin. This is the most common type of amyloidosis. AL amyloidosis can occur with a bone marrow cancer of plasma cells called multiple myeloma (fewer than 20% of AL patients). AL amyloidosis, including multiple myeloma cancer, is not associated with any other diseases but is a disease entity of its own, conventionally requiring chemotherapy treatment. Researchers have demonstrated the benefits of stem-cell transplantation therapy for AL amyloidosis. In stem-cell transplantation, doctors harvest the patients' own stem cells and store them while the patient receives therapy and then uses them to treat AL amyloidosis by replacing the abnormal plasma cells in the bone marrow.

AA amyloidosis (secondary amyloidosis)

When amyloidosis occurs secondarily as a result of another illness, such as chronic infections (for example, tuberculosis or osteomyelitis) or chronic inflammatory diseases (for example, rheumatoid arthritis and ankylosing spondylitis), the condition is referred to as secondary amyloidosis or AA amyloidosis. The amyloid tissue deposits in secondary amyloidosis are AA proteins. The treatment of patients' AA amyloidosis is directed at treating the underlying illness in that particular patient.

Familial amyloidosis (hereditary amyloidosis)

Familial amyloidosis (ATTR, AApoAI, AApoAII, AGel, ALys, AFib) is a rare form of inherited amyloidosis. It is more common in patients of African descent. The amyloid deposits in most familial amyloidosis are composed of the protein transthyretin, or TTR, which is made in the liver. Familial amyloidosis is sometimes referred to as hereditary transthyretin-mediated or HTTR amyloidosis. Familial amyloidosis is an inherited autosomal dominant in genetics terminology. This means that for the offspring of a person with the condition, there is a 50% chance of inheriting it. This form of amyloidosis is also referred to as hereditary amyloidosis. This type of amyloidosis can affect the nerves and the heart.

Beta-2 microglobulin amyloidosis (dialysis amyloidosis)

Beta-2 microglobulin amyloidosis occurs when amyloid deposits develop in patients on dialysis with longstanding kidney failure. The amyloid deposits are composed of beta-2 microglobulin protein and are often found around joints.

Localized amyloidosies

The many forms of localized amyloidosis are a result of amyloid deposits in specific areas of the body and are distinct from systemic forms of amyloidosis that deposit amyloid throughout the body. Localized amyloid deposits occur in the brain from Alzheimer's disease. In various tissues, often with aging (senile amyloidosis), amyloid can be locally produced and deposited to cause tissue injury. Prions are infectious amyloid proteins that transmit the diseases kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome.

Amyloidosis is caused by changes in proteins that make them insoluble, leading them to deposit in organs and tissues. These amyloid proteins accumulate mainly in the tissue space between cells. Changes in proteins that make them amyloid proteins occur because of gene mutations in DNA within cells.

Risk factors for the inherited forms of amyloidosis are being genetically related to an ancestor with the disease. The risk factors for secondary amyloidosis are the underlying inflammatory chronic medical conditions.

Age is a risk factor for amyloidosis, as well, as most people who develop amyloidosis are over 60 years old.

Male gender is a risk factor for amyloidosis as about 70% of people with AL are male.

Symptoms in patients with amyloidosis result from abnormal functioning of the particular organs involved. There might be no symptoms until the disease is relatively advanced. The heart, kidneys, liver, bowels, skin, nerves, joints, and lungs can be affected. As a result, symptoms and signs are vague and can include fatigue, shortness of breath, weight loss, lack of appetite, numbness, tingling, carpal tunnel syndrome, weakness, hearing loss, enlarged tongue, bruising, and swelling of hands and feet. Amyloidosis in these organs leads to cardiomyopathy, heart failure, peripheral neuropathy, arthritis, malabsorption, diarrhea, and liver damage and failure. Amyloidosis affecting the kidney leads to "nephrotic syndrome," which is characterized by severe loss of protein in the urine and swelling of the extremities.

Blood tests and urine tests can be used to look for abnormal proteins (light chain proteins) that could indicate amyloidosis.

The definite diagnosis of amyloidosis is made by detecting the characteristic amyloid protein in a biopsy specimen of involved tissue (such as mouth, rectum, fat, kidney, heart, or liver). A needle aspiration biopsy of fat just under the skin of the belly (fat pad aspiration), originally developed at Boston University, offers a simple and less invasive method to diagnose systemic amyloidosis. Pathologists (physician specializing in examining tissues) can see the protein in the biopsy specimen when it is coated with a special dye, called Congo red stain.

Once the diagnosis is made, tests of the involved organs can help establish the extent of the disease.

Amyloidosis can affect many different body systems and organs. Therefore, many different health specialists might be involved in the care.

Health care professionals who can be involved in the care of patients with amyloidosis include hematologists, nephrologists, cardiologists, rheumatologists, pulmonologists, neurologists, pathologists, and internists.

There is no cure for amyloidosis. The treatment of amyloidosis depends on the type of amyloidosis involved. Initial treatment of amyloidosis involves correcting organ failure and treating any underlying illness (such as myeloma, infection, or inflammation). The disease is frequently discovered after significant organ damage has already occurred. Therefore, stabilization of organ function is an initial target of treatment. The most frequent cause of death in systemic amyloidosis is kidney failure.

Treatment depends on the overall health of the patient and options include chemotherapy agents usually used for certain cancers and dexamethasone for its anti-inflammatory actions.

Sephardic Jews and Turks inherit a genetic disease called familial Mediterranean fever, which is associated with amyloidosis and characterized by episodes of "attacks" of fever, joint, and abdominal pains. These attacks can be prevented with the medication colchicine (Colcrys). Armenians and Ashkenazi Jews also have a higher incidence of familial Mediterranean fever attacks but do not suffer amyloid deposition disease.

Doctors can treat patients with AL amyloidosis (previously referred to as primary amyloidosis) who have reasonable underlying health with a cancer chemotherapy medication (melphalan [Alkeran]) in conjunction with bone-marrow stem-cell transplantation. These treatments attack the abnormal plasma cells in the bone marrow that are causing the AL amyloidosis. The results have been promising, and this combination treatment is offered to eradicate the amyloidosis in selected patients, provided that the underlying medical condition of the patient is adequate. These aggressive treatment options with stem-cell transplantation and high doses of chemotherapy are a true breakthrough in the treatment of patients with this form of amyloidosis. Other treatments include bortezomib (Velcade), cyclophosphamide (Cytoxan), and dexamethasone. For patients whose disease relapses or does not respond to initial treatments, clinical trials are available using ixazomib (Ninlaro) and monoclonal antibodies, such as daratumumab (Darzalex) used in multiple myeloma treatment. Other treatments include lenalidomide, pomalidomide, thalidomide, and dexamethasone.

Familial ATTR amyloidosis can now be cured with liver transplantation. This treatment option requires an accurate diagnosis of the specific protein that causes the disease.

Renal amyloidosis can be treated by kidney transplantation (renal transplantation).

Complications of amyloidosis are a function of what organs and tissues are affected and to what degree their function is impaired. Amyloidosis can lead to failure of lung, liver, heart, nerves, and kidney function. Additionally, the treatments (including chemotherapy as well as stem-cell and organ transplantation) can have serious side effects.

The outlook depends on the form of amyloidosis and its response to treatment. Systemic amyloidosis is slowly progressive and fatal if untreated. The average survival for AL amyloidosis is now years but significantly depends on what organs are affected. When the heart is involved, the survival decreases. Familial amyloidosis can survive well into the second decade. Again, the outlook and life expectancy is adversely affected by vital organ involvement.

There is no prevention for amyloidosis. However, the secondary forms of amyloidosis can be prevented by treating the underlying diseases that are associated with inflammation. Genetic counseling can be beneficial in familial amyloidosis.