What are the forms of amyloidosis? There are different forms of amyloidosis, distinguished by the type of proteins that make up the amyloid fibrils:

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1 Amyloidosis What is amyloidosis? Amyloidosis is characterized by deposition of abnormally aggregated or clumped proteins between cells that make up an organ. These aggregates or protein clumps are called amyloid fibrils. They can be deposited in only one organ, such as the skin, urogenital-, or respiratory tract, or more widespread in the body and then most often impair the function of one or more of the following organs: Kidneys, heart, liver, GI tract, and peripheral nerves. What are the forms of amyloidosis? There are different forms of amyloidosis, distinguished by the type of proteins that make up the amyloid fibrils: AL (amyloid light chain) amyloidosis. Previously this was called primary amyloidosis. The deposited proteins, called light chains, are a building block of antibodies and produced by abnormally growing and / or surviving immune cells. Sometimes these cells cause additional problems and are then considered cancerous. The cancer most frequently caused by these cells is called multiple myeloma, which is further explained in a separate document. Senile or age related amyloidosis. Here, a normal blood protein, usually a protein called transthyretin, is abnormally deposited in tissues for unknown reasons. Most often it is diagnosed when these proteins are deposited in the heart, but other organs can be involved as well. Familial or hereditary amyloidosis. There are several genetic changes or mutations known that result in the production of blood proteins with altered chemical properties leading to their aggregation and deposition in tissues. The most commonly affected protein is again transthyretin. Inflammatory amyloidosis. This was previously called secondary amyloidosis because it is a secondary problem of chronic inflammatory processes. Crohn s disease, rheumatoid arthritis, chronic infections and other inflammatory states go together with production of inflammatory proteins that float in the blood and in rare cases are deposited as amyloid in tissues. Hemodialysis related amyloidosis. This is caused by deposition of a blood protein called beta-2 microglobulin. The kidneys are the only organs that can get rid of this protein and with end stage kidney disease very high levels can be seen, that over time (usually over more than 5 years) can lead to amyloidosis. In recent years this type of amyloidosis is decreasing in incidence with improvement of dialysis techniques that help keep the beta-2 microglobulin concentration lower. What causes amyloidosis? The cause for genetic or hereditary amyloidosis is a heritable genetic alteration. For the other types of amyloidosis it is not clear why some people develop the disease whereas the majority of individuals do not, even if they share the underlying condition. Is amyloidosis a form of cancer? Generally amyloidosis is not considered cancer but light chain amyloidosis can go together with cancers of immune cells that produce antibodies or pieces thereof in an unregulated fashion.

2 What are the signs and symptoms of amyloidosis? Symptoms of amyloidosis usually develop long after amyloid starts being deposited. In addition symptoms are not specific, often leading to a delay in diagnosis. Commonly seen symptoms include the following. Any symptom can occur alone or in combination. Weakness or fatigue Weight loss Symptoms related to deposition in the heart - Shortness of breath, sometimes with cough and / or chest pressure - Swelling of the feet and legs (edema) - Irregular heart rhythm - Lightheadedness or even passing out due to low blood pressure Symptoms related to deposition in the kidneys (they usually first become leaky for proteins, leading to loss of the blood protein albumin. Albumin is needed to keep fluid in the blood vessels. Later the clearance of metabolic waste products from the blood can be impaired.) - Swelling of the legs (edema), abdomen (ascites), and, in the morning, of the eyelids - Shortness of breath - Decreased energy level - Anemia (low hemoglobin level) Symptoms related to deposition in or around the peripheral nerves or the nerves that innervate the heart, blood vessels, and gastro-intestinal tract - Abnormal sensations (tingling, sometimes pain) or numbness in the extremities - Lightheadedness or even passing out upon rising from bed or chair - Nausea, vomiting - Bloating, diarrhea, constipation Symptoms related to deposition in the gastro-intestinal tract - Enlarged tongue - Difficulty swallowing - Nausea and vomiting - Diarrhea or constipation - Bleeding (tar-like stool, red stool, or vomiting of coffee-ground-like material) Symptoms related to deposition in the liver - Early satiety - Abdominal swelling (from large liver or fluid accumulation) - Tendency to bleed - Altered mental state (extreme fatigue, confusion) Skin changes (easy bruising especially around the eyes, non-itchy rash, unusual sores or bumps, or thickening of the skin) Symptoms related to deposition in or around the lungs (uncommon) - Cough - Shortness of breath

3 Changes in vision (caused by amyloid deposits behind the lens of the eye) Nail changes Unusual hair loss Swelling of the lymph glands (uncommon) Symptoms related to deposition in the genitor-urinary tract (may be seen in localized amyloidosis) - Blood in the urine - Difficulty voiding - Burning on urination - Pain or dysfunction with sexual intercourse How common is amyloidosis? Amyloidosis is a rare disease, with an estimated incidence of around 10 cases per 1 million person-years. Among the diagnosed cases senile amyloid appears to be followed by light chain amyloid in the most recent reports (formerly light chain amyloid was felt to be the most common form). The other types of amyloid are even rarer. Amyloidosis is usually diagnosed later in life but especially genetic amyloidosis can also lead to symptoms in younger individuals. How is amyloidosis diagnosed? The diagnosis of amyloidosis requires confirmation of amyloid deposits through biopsy and analysis of the protein that is being deposited. Since the symptoms are not specific and the disease is a rare one, it is not uncommon that the diagnosis is delayed for several months, sometimes years, after the symptoms are first brought to medical attention. What additional tests are needed? In light chain amyloidosis, additional blood and urine tests are required and a bone marrow biopsy as well as x-rays of the bones are necessary to rule out multiple myeloma. Screening tests to determine which organs are involved include blood tests, a 24 hour urine collection and an ECG. Organs felt to be involved based on symptoms and screening tests may need further tests like an ultrasound of the heart or the liver, sometimes and endoscopic examination of the gastro-intestinal tract, or a CT of the chest to evaluate the lungs. Consultation with specialists for the respective involved organs help optimize care further. How is amyloidosis treated? This depends on the type. Localized amyloidosis is treated with local measures, usually resection with laser beams. The more common systemic forms are treated differently depending on the amyloid type. This can sometimes cure the disease, sometimes repeated procedures are necessary. The treatment of light chain amyloidosis is based on treatment of the cells that produce the deposited light chains. This can be done with cortisone-like steroids, new drugs effective in myeloma as well, and chemo, low-dose as outpatient or very high dose inpatient followed by a rescue from associated bone marrow depletion with stem cells that are collected from the blood prior. All these measures can not cure the underlying disease but can suffice to significantly reduce or abrogate the light chain production and thus prevent worsening or deposition in additional organs in the majority of patients for

4 varying periods of time. Once the light chain production is well controlled it usually remains controlled for months to years. When it comes back an alternative treatment regimen often controls it again. The organ function of involved organs can improve also over many months but this can not be guaranteed, since it happens in only in about 30% of patients. It is dependent on the severity of involvement, the more advanced the organ damage, the more likely scarring has occurred, which is irreversible. Additionally this is dependent on the involved organ, the kidney and liver, if not severely involved have relatively good chances for recovery, in some studies up to 50%. Senile amyloidosis currently is treated predominantly symptomatically; usually this means drugs that are given for heart failure. A treatment of its cause is not possible but clinical trials are underway that test the ability of drugs to inhibit deposition of transthyretin, the protein that makes up amyloid fibrils in patients with this disease. Genetic or hereditary amyloidosis. In most cases the genetically abnormal protein that is deposited as amyloid in this disease is produced in the liver. Liver transplantation in patients who are felt fit enough for the procedure, is curative but does not undo irreversible organ damage. Patients without donor or not fit enough for liver transplantation may have an option for medical treatment in the future. At least in patients with a specific genetic alteration of transthyretin, a drug called tafamidis was able to reduce the progression of nerve damage compared to placebo. The proposed mechanism of this drug is stabilization and thus prevention of deposition of abnormal transthyretin. The drug is not FDA approved as of January 11, 2010 but could gain approval Inflammatory amyloidosis. Here the basic principle is that the inflammatory state should be treated to reduce the levels of inflammatory proteins and thus halt or reduce further deposition. With chronic infections the treatment consists of the appropriate antibiotics, but in the developed world auto-immune processes like Crohn s disease or other inflammatory states of unknown etiology are more common causes of this type of amyloid and require effective treatment with drugs that reduce inflammation. Inhibitors of the inflammatory protein tumor necrosis factor alpha have shown success in a variety of inflammatory amyloidoses, but sometimes drugs with fewer side effects like low doses of the gout medication colchicine can also be helpful. Just like in the other types of amyloidosis the main goal is to prevent progression. Existing organ damage requires symptomatic treatment, sometimes this means hemodialysis. Hemodialysis related amyloidosis. The main goal here is prevention and with the use of modern dialysis techniques and filters that help keep the beta-2 microglobulin concentration in the blood lower, this type of amyloidosis becomes rarer. In otherwise fit patients kidney transplantation can be helpful to prevent any worsening since it helps getting beta-2 microglobulin levels close to normal. What is the prognosis? Localized amyloidosis usually does not affect life expectancy but sometimes repeated procedures are necessary. Systemic amyloidosis is a chronic disease and usually progresses slowly over a number of years. The severity of the disease

5 depends on which organs are affected and how severely they are affected. It can be lifethreatening in severe cases and in other cases may not affect life expectancy if it is detected early enough and caused by an amyloid type that can be treated. Resources For more information or to schedule an appointment, please call: Debbie Hastings at The Amyloidosis Support Network and Amyloidosis Foundation supports patient education and research. You can visit their website at: The International Myeloma Foundation maintains a hotline for patients and others who need information about myeloma, its treatment and management. The hotline number is: