It is generally considered that the amyloidoses share common pathogenic mechanisms which lead to protein fibril formation and deposition. These mechanisms may include structural, metabolic, genetic and environmental factors which may be common to all forms of amyloidosis, but due to the sporadic nature of these diseases, not readily studied. Immunoglobulin (primary) amyloidosis, while the most common form of amyloidosis, is a sporadic disease and, therefore, can only be investigated on a case to case basis. Reactive (secondary) amyloidosis occurs in subjects with chronic inflammatory disease, but factors which predict amyloid formation and, therefore, which subject is going to be affected are not readily apparent. Alzheimer disease, while very common in the aged population, is unpredictable except for those rare forms of familial Alzheimer disease with characterized mutations in specific genes. Hereditary transthyretin amyloidosis has generally been considered a rare disease and the original impetus to study the pathogenesis of this disease was because it represented a human model of systemic amyloidosis.
1) Primary Amyloidosis
What is Primary Amyloidosis?
Primary amyloidosis is a disease caused by the abnormal accumulation of
protein molecules in body tissues. These proteins are fragments of immunoglobulin
(antibody) molecules which are normally present in the blood to give protection
against bacteria and other infectious agents. Normally, antibody molecules are
constantly being synthesized by cells of the immune system and then, after a
finite life span, degraded so that there is a balance between production and
In this way our active immune system protects our bodies from a constantly changing array of infectious bacteria and viruses. In primary amyloidosis a defect occurs in the immune system. Excessive amounts of certain antibody molecules are produced and fragments of these molecules get deposited in tissues. These tissue deposits, as they enlarge, damage normal tissues and cause the disease that we know as primary amyloidosis.
What causes primary amyloidosis?
The cause of primary amyloidosis is unknown. Since the amyloid protein comes from immunoglobulin molecules, it is possible that some response of the immune system to an infectious bacteria, virus or other foreign substance may trigger the overproduction of antibody protein. So far this is only speculation, because amyloid has not been known to be associated with any particular infection. Indeed, there are no epidemiological data to suggest that amyloid occurs as result of infection. More is known about how the antibody molecules are deposited in tissue and lead to the disease. It is known that antibody molecules are made only by certain cells in the immune system called plasma cells. It is known that plasma cells can synthesize large amounts of antibody molecules but are usually under regulatory mechanisms that maintain a balance.
In primary amyloidosis this balance is disturbed and certain plasma cells synthesize antibody proteins in excess amounts. These proteins, as they circulate through the blood, move out of the blood vessels into tissues where they are polymerized as amyloid deposits. These deposits, which can occur in practically any organ of the body, continue to enlarge until they interfere with normal body functions. If the deposits are in the kidney, they will cause the kidney to have decreased function in getting rid of waste products and eventually the kidneys will fail to meet the body's needs. If the deposits are in the heart, the heart will have increased difficulty pumping blood and eventually heart failure will occur. If the deposits are in the nerves, a neuropathy will develop with loss of sensation to extremities and motor function to the muscles. Practically all organs in the body can become involved including the stomach and intestines, liver, spleen, skin and lungs. Usually the brain is spared, presumably because there is a "blood brain barrier" which restricts the movement of antibody molecules into the central nervous system.
Who gets primary amyloidosis?
Primary amyloidosis is an uncommon disease but because it causes symptoms which are similar to many other diseases (for example, nephritis, atherosclerotic heart disease, cancer and gastrointestinal disease), the diagnosis is frequently missed and the true incidence cannot be determined. Primary amyloidosis affects both men and women and has been reported to occur in individuals from the 20's to the later decades of life. The peak occurrence is around age 60-65 but many patients get the disease in their 40's and 50's.
What happens in primary amyloidosis?
Although amyloid proteins can deposit in any organ that has unrestricted blood supply, accumulations of amyloid protein in certain organs will cause illness much faster than others. For example, large amounts of amyloid can be present in the spleen without giving significant symptoms. It is well known that the spleen can be surgically removed and the body can function without problems. Small deposits of amyloid in the heart, however, can cause disruption of the electrical system that makes the heart beat and can be extremely life threatening. The most common organs to suffer from amyloid deposits are the kidney, heart, and liver.
The diagnosis of primary amyloidosis can only be firmly established by tissue biopsy. By sampling a small amount of tissue from an affected organ, the amyloid deposits can be demonstrated with special stains on microscopic sections of the tissue. Of course, a tissue biopsy of the organ involved with amyloid deposits would give the greatest chance of making the definite diagnosis, but often biopsy of affected organs is not easy to accomplish without risk. For instance, there is a certain amount of risk to having a heart biopsy, although biopsy using a catheter as is used for cardiac catheterization studies makes this more easily done. Biopsies of liver or kidney can result in bleeding which is an unwanted and potentially life threatening complication. For these reasons, biopsies of rectal mucosa through a sigmoidoscope or a biopsy of the skin are often used as the first test in confirming the diagnosis of amyloidosis. If the rectal mucosa or skin biopsy is positive for amyloidosis, then the doctor can assume that abnormalities affecting internal organs are due to the amyloidosis. Certain other tests are used to diagnose amyloidosis and, while suggestive of this condition, are not definitive. A large majority of patients with primary amyloidosis have evidence of abnormal antibody molecules in the blood stream and these can be demonstrated by certain tests. Echocardiograms, electrocardiograms, x-ray studies can suggest the diagnosis of amyloidosis and can be helpful in evaluating the patient.
Primary amyloidosis is usually a progressive disease which in the majority of patients leads to death from kidney or heart failure. There are not good data on how long a patient may have amyloidosis before it reaches the point where sickness from organ dysfunction commences, but there are fairly good data that show that the life expectancy after diagnosis is in the range of 1 to 1-1/2 years. Of course there are persons who live several years with primary amyloidosis and there are patients who succumb to the disease within a few weeks after the diagnosis is made. Most of these latter patients have, in retrospect, been ill for some time but the diagnosis was not made either because the patient did not seek medical help or the symptom complex was not typical for amyloidosis and the diagnosis not made.
There is no specific treatment for primary amyloidosis that has been proven to be effective and results in prolonged survival. A number of treatment modalities including special diets, vitamins, DMSO have been tried without any positive results. In some patients, treatment with high doses intravenous melphalan followed by bone marrow stem cell rescue (autologous bone marrow transplant) has proven effective. This therapy however is not indicated for patients with severe heart amyloidosis or extensive disease in other organs. The most common treatment for primary amyloidosis that is used by physicians includes chemotherapy consisting of Alkeran (Melphalan) and Prednisone. These drugs have been shown to be effective in the treatment of multiple myeloma which is also a disorder of the immune system but which is generally considered to be a malignant disease. Some studies have suggested that chronic treatment with Colchicine, which has been used for many years for the treatment of gout, may slow down the progress of primary amyloidosis.
While there is not specific treatment for primary amyloidosis, many of the manifestations of amyloidosis can be treated effectively. These include the use of diuretics to correct the abnormalities of kidney and heart failure. Antibodies may be of help in treating the gastrointestinal manifestations of amyloidosis. Kidney dialysis has been used for patients whose kidney function has been reduced below the levels needed to sustain life.
research is being done to find the cause and prevention of primary amyloidosis.
These studies are aimed at defining the mechanisms that are disrupted so that
the immune system is not in balance. Other studies are aimed at
determining how fragments of antibody molecules are polymerized to make amyloid
deposits. With knowledge about these mechanisms of amyloid formation, it
is hoped that specific therapies for treating primary amyloidosis can be devised
and that the deposition of amyloid material in tissues can be halted. In
addition to these basic forms of research, newer therapies are being tried to
see if the progression of amyloid formation can be altered.
2) Hereditary Amyloidosis
What is Hereditary Amyloidosis?
Hereditary transthyretin (TTR) amyloidosis is a predictable disease. Gene mutations are detectable from birth. Expression of variant plasma transthyretin proteins can be studied in individuals before amyloid onset, and these variant transthyretin proteins can be isolated or synthesized for studies of structure and fibril forming potential. In addition, transgenic animal models of human transthyretin amyloidosis are producing valuable information about the human disease. In other words, study of the pathophysiologic mechanisms of transthyretin amyloidosis has great potential for understanding amyloid fibril formation in general, and this may have a magnified impact on the health of the many people afflicted with different types of amyloidosis.
There is, however, an increased need to study the transthyretin amyloidoses on the basis that these are not as rare as originally thought. In recent years it has become obvious that there are many kindreds worldwide with transthyretin amyloidosis, there are a much larger number of mutations in transthyretin than originally appreciated, and it is now generally accepted that senile cardiac amyloidosis can result from deposition of amyloid fibrils made from normal transthyretin and this is an age related phenomenon. Also, one particular mutation of transthyretin (isoleucine 122) has a very high prevalence in the American Black population and can be implicated in congestive heart failure of a large number of individuals.
Therefore, we have two major objectives for our research:
1) to understand the pathophysiology of transthyretin amyloidosis so that means to treat or prevent the disease can be found, and
2) continue our study of this disease so that we may be able to extrapolate our findings to the other forms of amyloid fibril deposition.
At the present time the only specific therapy for this autosomal dominant disease is liver transplantation which results in elimination of the variant transthyretin. However, this is not a readily available and practical treatment for a large number of affected persons, and recent reports of progression of disease after liver transplantation in some individuals indicate that other forms of therapy are needed. To develop means of treating transthyretin amyloidosis it is important to understand pathogenesis so that methods of intervention may be devised to alter or prevent the disease.
Studies to date have centered on testing the hypothesis that single amino acid substitutions in transthyretin proteins lead to amyloidosis by affecting a change in the secondary and tertiary structure of the protein and that this alters both the metabolism of the molecule and its fibril forming potential. These studies have lead to hypothesized mechanisms of transthyretin fibril formation, but no definitive pathogenic mechanisms have been defined.
a) TTR mutations:
Transthyretin amyloidosis (reference article for professionals) (click to download in word)
b) TTR 3D representation
c) TTR gene sequence
d) Information for patients and family