About the diseaseWhat is amyloid?
All proteins have to fold in an appropriate way to function. Amyloid is an abnormal folding state of a usually otherwise normal protein. This abnormality makes the protein prone to aggregate into long, very thin threads (fibrils) which are difficult for the body to eliminate and which therefore tend to accumulate in certain organs and tissues. There are many different proteins that can make amyloid in man and each of the proteins is linked to one or a few specific disorders.
Amyloid can either occur in one organ and is then called ‘localized’ or is spread to many different organs and tissues. This latter group is called systemic amyloidosis. The systemic amyloidoses are usually serious diseases and may be life-threatening. They should be treated as early as possible and therefore an early diagnosis is important. In the systemic amyloidoses, the protein that forms the amyloid is produced at one or several sites in the body, transported via the blood and then deposited as amyloid in different organs by mechanisms that still have to be clarified. Depending on in which organs are affected, symptoms vary widely.
The systemic amyloidoses are relatively rare diseases but probably more common than believed. AL-amyloidosis seems to have about the same frequency in different parts of the world. AA-amyloidosis, however, may be more common in eastern Europe as compared to west Europe and the USA. Familial amyloidoses are spread all over Europe but more common in certain areas such as northern Portugal and northern Sweden. Systemic amyloidosis can develop at any age but is very rare before the age of 20. Most individuals get the disease after the age of 50 but the age varies depending on type of amyloidosis.
As mentioned, there are several different proteins that can make amyloid but there is usually only one protein in each disease. The systemic amyloidoses may develop as such or occur as a complication of an already existing disorder. The following describes the most common systemic amyloidosisAL-amyloidosis
In this disease, earlier usually called primary amyloidosis, one kind of antibody-producing cell (plasma cell) increases in number and secretes an abnormal amount of a part of the antibody, called light chain (the ‘L’ in AL; A stands for amyloid). This can happen without serious consequences but if this light chain has a strong tendency to aggregate, amyloidosis develops. Since the amyloid-forming light chains vary from individual to individual, there are differences between patients in how this amyloid form behaves. In some instances, amyloid tends to deposit in kidneys, in another patient in the heart and in a third perhaps in the liver. The variability is enormous as are the clinical consequences. The kidney involvement can lead to proteinuria and finally renal insufficiency. The heart amyloid may give rise to conduction disturbances or heart failure and the liver deposits to an enlarged liver. There are many more symptoms that may be seen. This variability often makes the diagnosis difficult. Treatment is primarily directed against the plasma cells responsible for the protein.AA-amyloidosis
This form, previously called secondary amyloidosis, develops as a consequence of a chronic and severe inflammatory malady, e.g. tuberculosis or rheumatoid arthritis, the latter today the most common cause. The amyloid protein comes from a liver product called ‘serum amyloid A’ (SAA) which is a normal blood protein occurring at higher concentration in conjunction with many inflammations. Usually AA-amyloidosis develops only after very long-lasting inflammation, 10 years or more, with persistent high blood concentration of SAA. This disease is particularly characterized by kidney problems and has become more uncommon during the last decade depending on the more aggressive treatment of rheumatoid arthritis. Treatment is directed against the inflammatory disease which leads to depression of the SAA protein, which stops new production of amyloid.Familial amyloid forms
Most commonly, the systemic amyloidoses are not inherited and there is no increased risk for a family member to develop the disease. There is however, a large but rare group of systemic amyloidosis where a mutation of a gene of a protein leads to a small but important alteration of its folding and makes it prone to form amyloid. This tendency is then inherited but for many of the genetically determined amyloids, not all individuals with the gene will develop disease. Presently the reasons for this variability are unknown.
Systemic amyloidosis associated with mutation in the gene for transthyretin
The most common forms of familial amyloidosis depend on mutations in the gene for the blood protein transthyretin. There are many different such mutations which are linked to amyloidosis, some associated with nerve symptoms (‘familial amyloidotic polyneuropathy’), others particularly with symptoms from the heart. Other consequences such as impairment of vision due to amyloid deposits in the vitreous of the eye may occur. It is important to underline that it is common to be a healthy carrier of the gene for transthyretin amyloidosis. As a matter of fact, for some mutations, most individuals do never get the disease. The reason for this is still unknown.
Systemic amyloidosis associated with mutation in the gene for other proteins
Most often familial amyloidosis is associated with mutation in the transthyretin gene but there are other, more rare forms in which mutations alter the folding of other proteins. The symptoms in these diseases may vary but problems with peripheral nerves, kidney disease or enlarged liver may occur, to mention a few.
Generally, a tissue sample (biopsy) needs to be taken for a microscopical analysis for a definite diagnosis. The biopsy can be obtained from an organ giving symptoms, e.g. from a kidney but more commonly the sample is taken from an easily accessible tissue, known to be the site of amyloid in all or at least most cases of systemic amyloidosis. Blood vessels in the gastrointestinal tract are almost always involved and this is the basis for the commonly used rectal biopsy. Another, more convenient site is the subcutaneous fat tissue over the abdomen where small amounts of amyloid usually are present in most forms of systemic amyloidosis. The tissues are either fixed in certain solutions, embedded for preparation of microscopical slides and sectioned, or directly spread on a microscopical glass slide. The material is then stained and examined in a special microscope which will give a definite diagnosis. It should be underlined that this is not an easy evaluation and an experienced evaluator is crucial.
The general diagnosis ‘amyloidosis’ is no longer sufficient but knowledge about the biochemical nature of the amyloid is necessary for treatment. This may be obtained in different ways. Often the clinical situation gives a very good information regarding type of amyloidosis. However, it is generally recommended that a direct biochemical analysis is performed and there are several ways to do this. For the familial amyloidoses, a genetic analysis is of great value.
The tissue biopsy does not give any information regarding the involvement of different organs, the severity of the disease or effects of treatment. For this, a method has been developed at which a radioactively (non-hazardous) labeled protein (SAP), which binds specifically to all amyloid, is injected in the blood. The bound SAP can then be traced and the distribution of the amyloid in the body is determined. Effects of treatment can then be determined.
Further clinical evaluation
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