Amyloidosis

Clinical Description

Amyloidosis is a group of related diseases in which a complex protein called amyloid builds up in one or multiple organs such as the kidney, heart, central nervous system, and/or the liver. As the protein accumulates, it interferes with organ function, and eventually causes the affected organs to fail. Each year, 3,000 cases of amyloidosis are diagnosed in the United States.

There are three major forms of amyloidosis.

• The most common form of amyloidosis is called immunoglobulin light chain or primary amyloidosis (AL). In patients with AL, abnormal plasma cells produce an amyloid-forming immunoglobulin light-chain protein. The median age at diagnosis is 63.
    
• Familial or hereditary amyloidosis (AF) develops among people who inherit a specific genetic abnormality. In the most common type of AF, the liver produces an abnormal form of a protein called transthyretin; treatment for this form of amyloidosis is liver transplantation.
  
• Secondary amyloidosis (AA), very rare in the developed world, is caused by inflammation resulting from either infectious chronic diseases (tuberculosis, bronchiectasis, osteomyelitis, leprosy) or inflammatory chronic diseases (rheumatoid arthritis, granulomatous ileitis). Treatment involves eliminating the source of inflammation.

 Symptoms of Amyloidosis

Symptoms include fatigue and weight loss, and may also include a feeling of fullness if the liver is involved; numbness and tingling in the lower extremities if proteins accumulate in the central nervous system; shortness of breath and dizziness on standing if the heart is affected; and fluid accumulation in the legs if the kidneys are affected.

Other common symptoms include: fatigue, numbness of hands and feet, weight loss, swallowing difficulties, irregular heart rhythm, bleeding into the skin, enlarged tongue, muscle spasms, joint pain, and hoarseness or changing voice.

About a third of people with AL have a significant amount of protein in their urine (a condition called albuminuria) and have few symptoms of organ involvement.

Another third have symptoms of protein accumulation in the heart -- shortness of breath when they exert themselves and abnormal findings on a heart study called an echocardiogram.

In a quarter of patients, the protein builds up in the liver and gastrointestinal tract, causing stomach discomfort on the right side, abdominal swelling, weight loss, early fullness with eating, and gastrointestinal bleeding.

About a fifth of patients experience peripheral neuropathy, which is degeneration of the nerves in the extremities, causing sensorimotor symptoms (decreased movement and sensation) that begin in the lower extremities.

Other symptoms include light-headedness with changes in position, diarrhea or constipation, and erectile dysfunction.

Risk Factors of Amyloidosis

Risk factors for different types of cancer are those traits that increase the likelihood that an individual will develop disease. The primary cause of AL amyloidosis is unknown, and therefore there are no known risk factors for the disease. Hereditary amyloidosis (AF) is genetic and should be suspected if patients present with symptoms of amyloidosis and they have a first degree family member who has had the disease. Genetic testing for the known types of hereditary amyloidosis is performed at Tufts Medical Center. The primary risk factor for AA amyloidosis is the presence of one of the chronic inflammatory conditions as described above.  Amyloidosis is more common in men than in women, and most people diagnosed are over age 40.

How Amyloidosis is Diagnosed

To diagnose amyloidosis, physicians use a number of tests including blood and urine studies, bone marrow studies, and a biopsy taken from an affected organ or a site rich in blood vessels (such as abdominal fat, the gums or gingiva, or the rectum). In over 95 percent of patients with AL, protein (free monoclonal light-chain) is found in the blood.

The diagnosis starts with a detailed clinical medical history and physical exam.  Symptoms similar to those described in the previous section and/or a family history of amyloidosis are discussed in the medical history.  On physical exam, the doctor will look for an enlarged liver or spleen, signs of heart failure, abnormal lung sounds and leg swelling. 

Once amyloidosis is suspected, multiple tests are often required to make a final diagnosis, including a tissue biopsy as noted above. Other tests include serum creatinine and blood urea nitrogen (BUN) to evaluate kidney function; alkaline phosphatase and other liver tests; B-type natriuretic peptide (BNP), which can be elevated if the heart does not pump correctly; and serum immunoglobulin levels, free light chains, and protein electrophoresis (SPEP), which check for abnormal proteins in the blood.  There are many other studies that are usually required as part of the diagnostic process for amyloidosis, including electrocardiogram, echocardiogram, lung tests, 24-hour urine collection, and bone marrow aspiration and biopsy. 

Treatment Options for Amyloidosis at Tufts Medical Center

Treatment for AL amyloidosis usually involves combination chemotherapy or stem cell transplantation to eliminate the abnormal plasma cells that make the immunoglobulin light chains causing the disease. For patients who cannot undergo stem cell transplantation, oral therapy with melphalan and dexamethasone is easily administered and is, in some respects, equivalent to melphalan-based stem cell transplantation. However, oral melphalan involves a risk of stem-cell injury and the development of myelodysplasia and secondary leukemia. For those in whom melphalan and dexamethasone are not effective, the novel agent Bortezomib is often used.

Tufts investigators have identified a number of unique aspects of amyloidosis, including the role that various genes play in the disease and the frequency with which patients have two different proteins that can cause amyloidosis. We have an active research program seeking to understand the genes in the abnormal plasma cells that cause AL amyloidosis. By studying the specific tissues that make the abnormal light chains we hope to unlock important secrets of this devastating illness over the coming years.

If you are a patient here, the team of doctors at Tufts may include your hematologist as well as a cardiologist, nephrologist and neurologist. Our Cancer Center offers treatment with medical therapy and stem cell transplant if indicated. There are several clinical trials opening at Tufts Medical Center that will study the efficacy of new drugs such as Bendamustine, Pomalidomide and new forms of Bortezomib-like agents in AL amyloidosis.

In certain cases, amyloidosis is treated with autologous or, in young patients who have exhausted other options, with allogeneic stem cell transplant.  Autologous stem cell transplant is a process by which a patient’s own blood stem cells are collected, cryopreserved in the stem cell laboratory, and then infused into the patient after he or she has received a high dose of chemotherapy. 

Allogeneic stem cell transplant is similar; however, the stem cells are taken from a matched related donor, a brother or sister.  The purpose of stem cell transplant process is to destroy the abnormal plasma cells in the bone marrow and replace them with healthy cells.  Both options are available at Tufts Medical Center.

Organ transplant, including kidney, heart and liver transplant, is an option for only a limited number of patients with amyloidosis.  Once amyloidosis is diagnosed, the treating physician will discuss the options that are available.

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