Transthyretin represents a transport protein for thyroid hormones found in all vertebrates. It is synthesized in the liver and in specific areas of the brain. Specific genetic alterations in transthyretin can lead to amyloidosis type 1 or ATTR amyloidosis.
What is transthyretin?
Transthyretin (TTR) is one of the transport proteins. Along with thyroxine-binding globulin (TBG), it is also a protein that binds thyroid hormones. However, its binding power is not as strong as that of TBG. For example, L-thyroxine (T4) is 99.99 percent bound to TBG, and triiodothyronine (T3) is 99 percent bound. Transthyretin binds with lower affinity to the thyroid hormone T4. There is no binding at all to T3. The half-life of thyroid hormones in the body is considerably increased by binding to the transport proteins, because their excretion in the urine is significantly delayed as a result. Thus, the half-life for T4 is about five to eight days. For T3, however, it is only about 19 hours because its binding to TBG is much lower and it does not bind to transthyretin at all. The total concentration of thyroid hormones depends on the concentration of the transport proteins. However, unlike the free ones, the bound thyroid hormones are not biologically active. Main sites of formation of transthyretin are liver and choroid plexus. The choroid plexus represents tangle-like arteriovenous vascular structures in the brain ventricles.
Anatomy and structure
Transthyretin is a protein molecule composed of 127 amino acids. Its secondary, tertiary, and quaternary structures are composed of homotetramers. The transport protein can be determined by serum electrophoresis. In this process, it appears before the albumin peak, which also earned transthyretin the alternative name prealbumin. Transthyretin has a molar mass of 55 kDa. The chemical structure of transthyretin allows its binding to thyroid hormones and to retinol. Because its concentration decreases during chronic inflammatory reactions, it is also known as an anti-acute-phase protein. Acute-phase proteins are produced in large quantities during inflammatory reactions. Thus, they are quickly available to the body during necessary defense reactions. However, the opposite is true for anti-acute-phase proteins such as transthyretin.
Function and tasks
The function of transthyretin is mainly to bind to and transport thyroid hormones. Together with TBG, it provides for its longer half-life in the organism. The thyroid hormones are inactive in the bound state, but they can be released at any time if needed. Another function of transthyretin is also to bind to retinol. In doing so, it forms complexes with the retinol-binding protein. Retinol is free vitamin A, which performs a variety of functions in the body. For example, it is responsible for the visual process and is involved in the function of the skin, mucous membranes, immune system, metabolism and blood cells. Both thyroid hormones and retinol are active only in the free form. However, their binding to transport molecules such as transthyretin prevents uncontrolled reactions of these active substances. Controlled release from binding with transport proteins ensures the orderly mode of action of these substances.
Diseases
Various mutations of transthyretin can cause both its deficiency and greater binding to thyroid hormones (hyperthyroxinemia). In hyperthyroxinemia, elevated total thyroid levels are present. But the concentration of free thyroid hormones is normal. Accordingly, normal thyroid function takes place. There are no symptoms. Hyperthyroxinemia is sometimes confused with hyperthyroidism (hyperthyroidism). The difference, however, is that in hyperthyroidism there is both an increased total thyroid concentration and a higher concentration of free thyroid hormones. However, amyloidosis type 1 (TTR amyloidosis) often occurs in association with transthyretin. It is often the result of a deficiency of transthyretin, which in turn is genetic. In amyloidosis, small protein fibers that are no longer soluble are deposited in the intercellular spaces, the interstitium. These fibers are in the form of so-called beta fibrils called amyloid.Amyloidosis is not an independent disease, but a collective term for several different diseases with pathological deposition processes. Depending on the cause, specific organs are affected by the deposition of defective protein fibers. In transthyretin-induced TTR amyloidosis, the heart, nervous system, intestines, eyes, lungs or kidneys, among others, may be involved. It can lead to cardiac insufficiency with cardiac arrhythmias, sensory disturbances in the hands and feet, diarrhea, constipation, weight loss or, in rare cases, severe kidney damage, including the need for dialysis. Since transthyretin is produced in the liver, liver transplantation can lead to a cure for this form of amyloidosis. The new healthy liver synthesizes normal transthyretin again. The deposition process comes to a halt. However, if the disease is more advanced, even liver transplantation cannot guarantee a cure. A special form of TTR amyloidosis is ATTR amyloidosis (senile amyloidosis). This form of the disease occurs particularly in old age. Here, too, the cause is to be found in genetic changes in transthyretin. Without treatment, amyloidosis leads to death within a few years. In addition to a causative liver transplant, symptomatic therapies must be carried out. These depend on which organs are particularly affected. If the heart is involved, diuretics and ACE inhibitors, among others, are administered. If cardiac arrhythmias occur, a pacemaker can help improve the situation. A diet low in salt is important. Low-salt diet, administration of ACE inhibitors and diuretics are also indicated in cases of renal involvement. Dialysis may become necessary if necessary.
