Information for patients and family

 

  • What is transthyretin amyloidosis?

Transthyretin amyloidosis is a disease caused by the abnormal accumulation of protein molecules in body tissues.  These protein accumulations or “amyloid deposits” are made from a blood protein, transthyretin, which normally transports thyroid hormone and vitamin A to the body tissues. When an inherited defect in the transthyretin protein occurs, this abnormal form of transthyretin has the tendency to accumulate in tissues such as the heart, kidneys, nerves, and intestine.  The presence of these deposits interferes with the normal functions of the organs, and as the deposits enlarge more tissue damage occurs and the disease (transthyretin amyloidosis) worsens.  

  • What is transthyretin?

Transthyretin is a normal blood protein.  Its function is to carry thyroid hormone and vitamin A to tissues where they are needed for normal metabolism.  Like all proteins transthyretin is made from the 20 different amino acids which are linked end to end to make large molecules.  Each protein is identified by the arrangement of the amino acids in the protein chain and this arrangement is determined (coded) by a specific gene.  In the case of transthyretin a single gene located on chromosome 18 codes for the amino acid alignment (sequence) which is characteristic of this protein and distinguishes it from all other proteins.

  • What causes transthyretin amyloidosis?

Transthyretin amyloidosis is caused by mutations in the protein.  A mutation occurs when the position of one amino acid in the protein chain is replaced by a different amino acid.  This causes a structural change in the protein molecule, and the protein then has a tendency to deposit in the tissues.  The protein that actually deposits in the tissues has changed its structure so that aggregation of many protein molecules makes fibrils (β-fibrils) which are very resistant to being dissolved or degraded by normal body functions.

  • Who gets transthyretin amyloidosis?

Transthyretin amyloidosis is an hereditary disease.  A mutation in the gene for transthyretin protein is passed from one generation to another.  It is an autosomal dominant disease which means that both men and women get the disease and that only one copy of the mutated gene is required to cause the disease.  An individual with a mutant form of transthyretin may have obtained the genetic trait from either their mother or father and they in turn are capable of passing the mutant gene on to their children.  Each child has an equal chance (50/50) of inheriting the mutant gene instead of the normal gene.  Transthyretin amyloidosis almost always occurs after age 20 and in most individuals the disease begins after age 50.  By that time most individuals with mutated transthyretin genes have had the opportunity to raise families and, therefore, have passed the gene on to their children before they themselves develop the clinical disease.

 

  • What happens in transthyretin amyloidosis?

While transthyretin amyloid deposits may occur in any organ, they most commonly affect the peripheral nerves, heart, intestine, and the kidney. For any one individual it is difficult to predict which organ will be involved to the greatest extent and, therefore, cause disease symptoms that will be recognized by the patient and their physician.  Amyloid involvement of the peripheral nerves most commonly causes numbness or tingling in the feet or hands at the beginning and then may progress to cause difficulties in walking or performing fine hand movements.  Involvement of the heart often causes congestive heart failure with tiredness, weakness, and swelling of the feet from water retention.  Involvement of the intestine may cause constipation, or diarrhea, or alternating constipation and diarrhea.  In some patients with specific forms of transthyretin amyloidosis, deposits of the protein occur in the eye and obstruct vision.  A few individuals developed deposits of amyloid in the linings around the brain and this may cause headache and stroke-like symptoms.

  • Diagnosis

The diagnosis of transthyretin amyloidosis can only be firmly established by tissue biopsy.  Biopsy of an affected organ such as peripheral nerve, intestine, heart, or kidney allows the demonstration of amyloid deposits with special stains on microscopic sections of the tissue.  First, however, it is necessary for the physician to suspect the diagnosis of amyloidosis so that a biopsy will be done.  For many individuals a family history will suggest that transthyretin amyloidosis diagnosis should be considered.  If an affected individual reports that their mother or father had a similar illness or was found to have amyloidosis when they died this will raise the likely diagnosis of amyloidosis.  The same is true if an affected person has a brother or sister who has the disease.  Now we have the ability to test the DNA of individuals suspected of having transthyretin amyloidosis and determine if they have one of the mutant genes which causes this disease.  By isolating DNA from a sample of blood, tests can be done to detect the genetic mutation associated with transthyretin amyloidosis.  In addition DNA tests can be done for any person  who wants to know if they have a transthyretin gene mutation that can cause the disease before they develop any signs.  This will allow that person to seek medical advice and counseling without being subjected to extensive medical tests for other diseases which might be suspected if the results of DNA analysis were not known.

  • Prognosis

Transthyretin amyloidosis is a progressive disease which usually causes increasing organ dysfunction over a time of several years.  The rate of progression varies considerably depending on which transthyretin mutation causes the disease.  Major causes of disability include bowel dysfunction with severe diarrhea and weight loss, congestive heart failure with generalized weakness and difficulties breathing from fluid retention. A smaller number of individuals develop kidney failure and require dialysis treatments.  It is not unusual for affected individuals to live 5, 10, 15, or sometimes even 20 years after the first signs of disease.

The only specific treatment for transthyretin amyloidosis is liver transplantation.  Transthyretin is made in the liver and if an individual receives a transplanted liver they no longer make the abnormal protein.  This procedure has been done for several hundred subjects.  Many have benefitted from liver transplantation and are able to live a relatively normal life; although the degree of organ impairment that occurred before the liver transplantation does not usually reverse. Unfortunately, some individuals continue to have progression of their disease after liver transplantation.  It is felt that after transthyretin amyloid deposits have started to occur in various organs, normal transthyretin protein may continue to be deposited without the mutant form of the protein being present any longer. 

The fact that liver transplantation is not available to many individuals, especially those at older age when transthyretin amyloidosis very often occurs, and the fact that liver transplantation is not curative for some individuals, it is important that we continue medical research to discover new ways of treating or preventing this disease.  At the present time studies are ongoing to develop therapeutic agents which might interfere with the formation of amyloid tissue deposits.  Other studies are aimed at methods to suppress the manufacture of abnormal transthyretin by the liver.  These studies are aided by the availability of transgenic animals (mice) that have been given the human transthyretin gene so that controlled studies can be done to test new types of treatment.  If these new treatments are effective in the animal models, then they may be applied to the treatment of the disease in humans.  No such naturally occurring model of transthyretin amyloidosis has been found in any animal species except humans, and, therefore, the use of laboratory animals to find a treatment for this disease is absolutely essential.

 

     TYPES OF SYSTEMIC AMYLOIDOSIS

 

TYPES

 

DISTINGUISHING FEATURES

 

CHEMICAL NATURE OF AMYLOID

 

Primary / Immunoglobulin

 

Sporadic occurrence

No predisposing factors

 

Immunoglobulin

(Antibody protein)

 

Secondary / Reactive

 

Occurs with chronic inflammatory diseases (Rheumatoid arthritis, Crohn=s disease)

 

Liver protein made during inflammation

 

Hereditary / Familial

 

Occurs in families with certain gene mutations.

 

Genetically abnormal proteins


TYPES OF FAMILIAL SYSTEMIC AMYLOIDOSIS

 

TYPE

 

DISTINGUISHING FEATURES

 

USUAL CLINICAL FEATURES

 

Transthyretin

 

Most common, worldwide

 

Neuropathy, Heart failure, Diarrhea, Kidney failure

 

Fibrinogen

 

United States, Europe

 

Hypertension, Kidney failure

 

Apolipoprotein AI

 

United States, Europe

 

Kidney failure

 

Lysozyme

 

Europe, Canada

 

Kidney failure, Liver failure

 

Gelsolin

 

Finland

 

Corneal changes (eye), Occasionally heart and kidney disease

 

Cystatin C

 

Iceland

 

Intra-cranial hemorrhage

 

Apolipoprotein AII

 

United States, Russia

 

Kidney failure

 

American College of Physicians:

http://pier.acponline.org/pierindex.html/hp