For Patients

A Patient Guide to Amyloidosis

Amyloidosis refers to a group of diseases, caused by deposits of abnormal proteins known as amyloid, affecting one or more organ systems in the body. Deposition of amyloid in the heart is known as cardiac amyloidosis. When this occurs, the heart becomes stiff; fluid buildup in the lungs leads to breathlessness; and fluid buildup in soft tissues causes leg or abdominal swelling. Below we present an overview of the general condition of amyloidosis and describe how it may affect various organs of the body, including the heart.

What is Amyloidosis?

Amyloidosis is a disease that typically affects many organs of the body simultaneously. It is caused by deposits of a protein-like material - amyloid - around the cells of these organs, leading to progressive damage to the affected parts of the body.

There are several types of amyloidosis, and it is very important that the correct type is identified, as treatment differs greatly for each form. Described below are the commonest types of amyloidosis and the organs that are most commonly affected.

• AL amyloidosis (primary amyloidosis)is a bone marrow disease that is closely related to a more common bone marrow disease, multiple myeloma. In AL amyloidosis, plasma cells produce an abnormal protein that is unstable and breaks down to form amyloid deposits in various tissues of the body. Men and women are equally affected and the disease is commonest after the age of 50, although it occasionally occurs in younger patients.

• Familial amyloidosis is usually inherited as an autosomal dominant disease. This means that it is inherited through either parent, and that each child of an affected parent has a 50-50 chance of inheriting the disease. It is most commonly associated with an abnormality in a protein called transthyretin (TTR), which functions normally until adult life and then - usually between age 30 and 60 - breaks down and causes amyloidosis. There are many different types of abnormalities (mutations) of TTR, but most are quite rare. However, 1 in 25 African-Americans carry this abnormality. While this puts these subjects at risk of amyloidosis, not all who have the abnormality develop the disease. When it does occur, it usually appears at around age 60-70, leading to progressive fluid retention due to impaired heart function.

• Secondary (AA) amyloidosis occurs in patients with chronic inflammatory disease such as rheumatic diseases or chronic inflammatory bowel disease. It usually causes liver or kidney problems and rarely affects the heart.

• Senile amyloidosis, in which the amyloid isderived from normal TTR,is aslowly progressive disease thataffects the hearts of elderly men. It may be one of the commonest forms of cardiac amyloidosis, but the diagnosis is often missed, either because the physician is unaware of the disease or because symptoms are attributed to other forms of heart disease.

• Localized amyloid deposits may occasionally occur in isolation without evidence of a generalized disease. Isolated bladder amyloid and amyloid in the trachea are the forms most commonly seen.

How common is amyloidosis?

Due to the almost certain presence of undiagnosed cases, it is difficult to estimate precisely how often the disease occurs. However, reliable studies have been done in AL amyloidosis, which shows that its frequency is approximately 1/5 of that of multiple myeloma. Based on this, it is estimated that there are between 1500 and 2500 new cases of AL amyloidosis annually in the United States. Familial and secondary amyloidosis are probably less common than AL amyloidosis, whereas senile amyloidosis is probably more common, but often not recognized.

What are the symptoms of amyloidosis?

As amyloidosis can affect one or more vital organs, a patient can have a wide spectrum of symptoms. This variation may make it difficult for a physician to suspect the disease, but early diagnosis is possible.

The first symptom to appear depends upon the organ or organs involved. The following are some of the commoner ways in which amyloidosis may manifest itself.

The Heart in Amyloidosis

Impaired heart function caused by amyloid deposition often results in excess build-up of fluid in the body. This condition, known as congestive heart failure, is associated with congestion in the lungs and liver. A patient with heart failure due to any type of heart disease often has shortness of breath, sometimes worse when lying down, and may have fullness or discomfort in the upper abdomen due to a congested liver. A careful physical exam by a physician, paying attention to the veins in the neck (which will be distended in most cases of amyloid heart failure), the sounds in the lungs, and careful examination of the abdomen (to determine whether the liver is enlarged), should make the diagnosis of heart failure in most patients. An aid to the diagnosis of heart failure in unclear cases of breathlessness is the  blood test known as BNP (short for B-natriuretic peptide) or nT-proBNP (n-terminal pro-B natriuretic peptide), which is elevated if shortness of breath is caused by heart failure.

The first sign of amyloidosis in the heart is occasionally a pressure or dull pain in the chest during exertion, which is typical of the condition known as angina. Most cases of angina are due to the blockage of one or more major arteries of the heart due to cholesterol deposits and are unrelated to amyloidosis. These cholesterol blockages can be seen with a test known as an angiogram. Amyloid deposits, however, tend to narrow the very small vessels of the heart, which are not seen on an angiogram. Therefore, if a patient with angina due to amyloidosis has an angiogram, he or she may be told that everything looks fine - even though the symptoms can be severe. However, careful measurement of the pressure in the left ventricle at the time of the test may show subtle elevations that suggest that there is indeed an abnormality present. An abnormally slow heart rate occasionally occurs due to amyloid’s effect on the electrical system of the heart.  Unusually low complexes on an electrocardiogram (also called ECG or EKG) in association with thick heart walls seen on an ultrasound of the heart (echocardiogram) are common clues to the existence of the disease.

The Kidney

If the amyloid affects the kidneys, it usually results in loss of protein (albumin) into the urine, a condition known as proteinuria. Albumin is a major component of egg white, and, just as mixing raw egg white with water and shaking it results in a foamy solution, so a patient with an albumin leak into the urine may notice foamy urine. As the protein loss continues, swelling of the ankles and legs may develop, which can be quite severe. A simple urine test, which can be performed immediately in any doctor’s office, can determine whether there is excess protein in the urine. Although this urine test will not determine the specific cause of the protein loss, further testing, which may include a kidney biopsy, can lead to diagnosis of the type of kidney disease and, in a patient with amyloidosis, will demonstrate the amyloid in the kidney.

Proteinuria may occur in the setting of otherwise normal kidney function so that the organ’s ability to function as a part of the body’s waste-disposal system remains intact. However, patients with amyloid kidney disease may occasionally experience kidney failure, with a buildup in the blood of waste substances produced by the body. An evaluation of kidney function can be made by a routine blood test to measure the blood urea nitrogen (known as BUN) and the blood level of creatinine. These are both elevated in kidney failure.

Nervous system

Damage to the nervous system, known as neuropathy, is less common than kidney or heart involvement, but can be a significant problem. It may occasionally be the initial and predominant feature of AL amyloidosis, and it may be the sole feature in certain types of familial amyloidosis. Neuropathy may result in loss of sensation in the hands or feet so that, for example, a patient has trouble buttoning clothes. A “pins and needles” sensation in the limbs may be troublesome, and, occasionally, there may be a sensation of pain. This type of neuropathy is referred to as “peripheral neuropathy.” In familial amyloidosis, the peripheral neuropathy is frequently accompanied by an autonomic neuropathy in which the nerves responsible for various organ functions are involved. Autonomic neuropathy may result in diarrhea or severe constipation, dizziness or loss of consciousness when standing up suddenly (due to a sudden and abnormal drop in blood pressure), and, in the male, sexual dysfunction. Although peripheral and autonomic neuropathy is commoner in familial amyloidosis, either or both can occur in a patient with AL amyloidosis.

A common form of local nerve damage found in all types of amyloidosis is “carpal tunnel syndrome.” This is a compression of the median nerve, a nerve in the hand, which results in pain and weakness in the hand. Carpal tunnel syndrome is not limited to amyloidosis, and it may precede other symptoms of the disease by one or more years. Thus, while carpal tunnel syndrome alone rarely is due to amyloidosis, a history of carpal tunnel syndrome in a patient with other symptoms possibly due to amyloidosis should act as an added clue to the diagnosis.

Amyloidosis does not involve the central nervous system, and thus mental function is unimpaired.

Liver and Digestive Tract

Disturbance in the functioning of the liver is common in AL amyloidosis and AA (secondary) amyloidosis, but is not seen in transthyretin-related, (familial or senile), amyloidosis. In most cases, there are no symptoms from amyloid liver disease, but the liver may be enlarged, occasionally markedly so. When liver enlargement is due to infiltration with amyloid rather than congestion from heart failure (see above), a skilled physician will notice that it feels very hard. An amyloid-infiltrated liver, even if not markedly enlarged, is frequently associated with abnormal elevation of a liver enzyme in the blood, known as alkaline phosphatase. Other commonly-measured liver enzymes, the transaminases, are often normal despite elevated alkaline phosphatase. Jaundice (a yellowing of the skin due to liver disease) is a marker of severe liver disease when caused by amyloidosis, but, fortunately, is rare. Liver amyloidosis rarely occurs in isolation and is usually associated with other organ involvement, particularly the kidneys.

Diarrhea in amyloidosis is most commonly related to the disturbance of the autonomic nervous system controlling the bowel. Occasionally, amyloid deposits anywhere in the intestine (stomach, small or large bowel) may result in bleeding, causing dark black or red stools. Loss of taste and difficulty eating solid foods because of an enlarged tongue (macroglossia) may contribute to weight loss, or weight loss may be a non-specific manifestation of the disease itself, particularly in AL amyloidosis. In patients with autonomic neuropathy, there is often a sensation of being full after only part of a meal has been eaten. This is due to impaired emptying of the stomach.

Soft Tissue and Skin

Certain skin abnormalities are seen predominantly in patients with AL amyloidosis, which may strongly suggest the diagnosis, particularly when other organ involvement suggests a generalized disease. The most typical feature, seen to some degree in about 25% of patients with AL amyloidosis, is the development of small bruises on the eyelids, which come and go. The patient may be unaware of any trauma to the eyelids, or may have noticed that the bruising may occur after rubbing the eyelids. Occasionally, a typical “black eye” may appear after coughing, sneezing or straining during a bowel movement. Unlike a black eye due to a blow to the eye area, the black eye of amyloidosis is not associated with swelling, so the eye itself is visible, giving an appearance of “raccoon eye(s)” (periorbital purpura). Periorbital purpura is a result of fragile skin capillaries (small blood vessels) and is virtually exclusive to AL amyloidosis. Soft tissue infiltration with amyloid deposits may cause enlargement of the tongue (macroglossia). Hoarseness, which may come and go during the day, may occur due to small amounts of amyloid in the vocal cords; in such cases, vocal cords often appear normal upon examination.

Lung Involvement

Amyloid may deposit in the lungs, particularly in AL or senile amyloidosis, but this rarely causes any problems. Occasionally, however, in AL amyloidosis, significant lung infiltration may occur, resulting in breathlessness. This almost invariably occurs in patients who also have significant cardiac involvement, making the precise cause of the breathlessness difficult to determine. Fluid around the lungs, known as pleural effusion, is quite common in patients with heart failure due to amyloidosis, but large pleural effusions that are disproportionate to the degree of heart failure and are difficult to treat suggests they are due to a large amount of amyloid in the lining of the lungs (the pleura). This is quite an uncommon feature of the disease.

Thyroid Gland

The thyroid is a gland in the neck partly responsible for the body’s metabolism. AL amyloidosis often affects the thyroid gland, making it underactive. The degree of thyroid involvement is relatively mild and is usually detected by an elevation in the blood test known as thyroid stimulating hormone (TSH). Occasionally, the thyroid may be significantly underactive, resulting in fatigue, skin changes, elevated cholesterol, slowed thinking, and sensitivity to cold. Whether involvement is mild or severe, the thyroid problem is usually simply treated with thyroid hormone replacement.

How is Amyloidosis Diagnosed?

It is critical to obtain a piece of body tissue to confirm a suspected diagnosis of amyloidosis. The process by which this is obtained is known as tissue biopsy, and its nature depends on the type of tissue obtained. A biopsy of the organ, or one of the organs suspected as being involved with amyloidosis, will give the highest yield, although amyloid deposits are found throughout the body in this disease, and, therefore, biopsy of an apparently uninvolved organ will often show amyloid deposits. This is the logic of performing a fat pad biopsy, a procedure in which a very small amount of fat from under the skin is sucked out with a needle for examination under a microscope. In skilled hands, a biopsy from almost any organ is safe and can be done with minimal discomfort.

In suspected amyloidosis of the heart, a cardiac biopsy is often performed. After numbing an area of the neck with a local anesthetic, a thin, flexible wire with a tiny pincer-like end, known as a bioptome, is passed through a vein into the right ventricle of the heart. The physician doing the procedure uses X-ray guidance to safely position the bioptome and to take four or five pinhead-size pieces of heart muscle. These are then examined by highly-trained pathologists for amyloid and other abnormalities after they have been stained with special stains. The classic amyloid stain is Congo red. When stained with this substance, and viewed under a special microscope that uses polarized light, amyloid deposits glow with an apple-green color. Another useful stain, particularly when seeking amyloid deposits in the heart, is known as sulfated Alcian blue, with which amyloid deposits reveal a turquoise-blue color (figure). The kidney and liver, both of which can be biopsied by using a needle, are also common sites for amyloidosis diagnostic biopsies. A skin biopsy of an area of skin suspected of involvement may also have a high diagnostic yield.

The standard staining for amyloid will only determine that amyloid is present, but will not distinguish the types of amyloid (AL, AA and transthyretin) from one another. It is very important to determine the type of amyloidosis, as the treatment of the various types differs greatly. There may well be clues as to the type of amyloidosis, such as a family history or the involvement of certain organs, but it is always critical to be as certain as possible about the type. As AL amyloidosis arises because of a bone marrow disorder, a bone marrow biopsy is usually performed. Special staining of the marrow can identify abnormalities in the plasma cells and can help to exclude the presence of multiple myeloma, a disease that overlaps with AL amyloidosis in about 1 in 20 cases. Blood and urine may need to be examined to determine the presence of an abnormal protein by using a test known as immunofixation. A specialized blood test, which may not be performed in every doctor’s or hospital’s laboratory (but which is easily obtainable through several commercial laboratories), known as the free light chain assay, will be abnormal in almost all cases of AL amyloidosis, and has proven useful in following the progress of treatment.

If these tests are negative in the setting of a positive biopsy for amyloid, a type of amyloid other than AL should be suspected. A blood test to evaluate abnormalities in the transthyretin molecule can be performed, and very rare mutations in other molecules that may cause amyloidosis can also be evaluated. In the absence of mutations of transthyretin, very rare forms of familial amyloid may be present. If the patient is an elderly man with clinically isolated cardiac involvement, the most likely diagnosis is senile systemic amyloid (senile cardiac amyloid), a condition in which amyloid derived from normal transthyretin is deposited in the heart.

Treatment

The type of treatment prescribed is dependent upon by the type of amyloidosis present, the age of the patient and his/her disease severity, and the preference of the treating doctor. In AL amyloidosis, treatment is aimed both at improving symptoms and getting rid of the production of the amyloid by destroying the abnormal plasma cells. Various types of therapy - usually chemotherapy - can be used, but the commonest include melphalan, given either orally or intravenously. In carefully selected patients, treated at centers with the appropriate expertise, high-dose intravenous melphalan with transplantation of the patients own stem cells derived from their marrow (a procedure known as autologous stem cell transplantation) has a reasonably high degree of success in stopping amyloid production. However, this treatment is associated with a significant risk in sicker patients, particularly those with involvement of the heart. In such patients, treatment with drugs taken by mouth is preferable. The specific drugs recommended will vary from patient to patient, but often consist of a few days therapy each month, followed by several days or weeks without drug therapy. Whatever dose regimen is recommended, a patient receiving treatment for AL amyloidosis should be followed carefully by a hematologist with experience in the disease. Supportive therapy, such as treatment of congestive heart failure, attention to nutrition, treatment of the effects of autonomic neuropathy, etc., is a very important part of therapy. Heart involvement in amyloidosis requires frequent follow-up with a cardiologist skilled in the management of heart failure. Because patients with cardiac amyloidosis of any form are often highly sensitive to salt intake, they should adhere strictly to a low-sodium diet, limiting salt intake to no more than 2000 milligrams (2 grams) daily. This requires reading nutrition labels on food carefully, not adding salt to food, and (usually) avoiding eating in restaurants. A consultation with a dietitian is a valuable exercise in learning to live with a low–sodium diet, and there are several good low-sodium cookbooks that contain excellent and tasty recipes.

Familial TTR amyloidosis is treated, if possible, by removing the source of the abnormal TTR production. Since the main source is the liver, liver transplantation is currently the treatment of choice in carefully selected patients whose disease is not too far advanced. Liver transplantation is a major operation, with a need for lifelong therapy to prevent organ rejection by the body’s immune system, and in patients with significant cardiac disease it may not be effective unless the heart is also transplanted. Intensive investigation is underway to develop and test drugs that can prevent the production of amyloid in patients with the abnormal gene. These drugs, if effective, may abolish the need for liver transplantation. They may also have the additional benefit of being effective in senile cardiac amyloidosis, a condition for which no specific treatment currently exists, other than treatment of the effects of the amyloid deposition in the heart.

The mainstay of secondary amyloidosis treatment is therapy of the underlying disease. Renal (kidney) transplant has been performed successfully for renal disease due to secondary amyloidosis. Eprodisate (Fibrillex) is a small molecule that inhibits the formation of amyloid fibrils (threadlike fiber), and which seems to have a modest clinical effect in patients with secondary amyloidosis. It is, however, not currently available for clinical use, pending further clinical trials of its efficacy.

Summary

Amyloidosis is a serious disease and its diagnosis and management is complex, requiring expertise on the part of the physicians involved, a collaborative approach among specialists, and an effort by the patient to carefully follow dietary and treatment-related advice. Patients with cardiac involvement are perhaps the most complex for a physician to treat, as the disease has somewhat unique features compared to many other forms of cardiac disease. The Brigham and Women’s Hospital/ Harvard Vanguard Cardiac Amyloidosis Program offers patients a team approach to the disease, and draws upon the international expertise of these Harvard Medical School institutions. By acting as a referral center for the evaluation of patients with all types of amyloidosis, with an emphasis on heart disease, combined with a commitment to detailed and ongoing communication with patients and referring physicians, whether locally, nationally, or internationally, we aim to provide the highest standard of medical and supportive care, combined with cutting-edge basic and clinical research and trials.